Non-imidazole alkylamines as histamine H3-receptor ligands and their therapeutic applications

ABSTRACT

Use of a compound of formula (A), wherein:  
                 
 
     W is a residue which imparts antagonistic and/or agonistic activity at histamine H 3 -receptors when attached to an imidazole ring in 4(5) position; R 1  and R 2  may be identical or different and represent each independently a lower alkyl or cycloalkyl, or taken together with the nitrogen atom to which they are attached, a saturated nitrogen-containing ring (i) as defined, a non-aromatic unsaturated nitrogen-containing ring (ii) as defined, a morpholino group, or a N-substituted piperazino group as defined for preparing medicaments acting as antagonists and/or agonists at the H 3 -receptors of histamine.

[0001] The present invention relates to alkylamines of formula (A) asdefined hereafter, to their preparation and to their therapeuticapplications.

[0002] Antagonists of histamine H₃-receptor are known especially toincrease synthesis and release of cerebral histamine, Through thismechanism, they induce an extended wakefullness, an improvement incognitive processes, a reduction in food intake and a normalization ofvestibular reflexes (Schwartz et al., Physiol. Rev., 1991, 71: 1-51).

[0003] Whence these agents are potentially useful in several centralnervous system disorders such as Alzheimer disease, mood and attentionalterations, cognitive deficits in psychiatric pathologies, obesity,vertigo and motion sickness.

[0004] Histamine H₃-receptor agonists are known to inhibit the releaseof several neurotransmitters including histamine, monoamines andneuropeptides and thereby exert sedative and sleep-promoting effects inbrain. In peripheral tissues, H₃-receptor agonists exert namelyanti-inflammatory, anti-nociceptive, gastro-intestinal, antisecretorysmooth muscle decontracting activities.

[0005] All the H₃ receptor antagonist or agonist compounds known so farresemble histamine in possessing an imidazole ring generallymonosubstituted in 4(5)-position (Ganellin et al., Ars Pharmaceutica,1995, 36:3, 455-468; Stark et al., Drug of the Future, 1996, 21(5),507-520).

[0006] Numerous patents and patent applications are directed toantagonist and/or agonist compounds having such structure, in particularEP 197 840, EP 494 010, WO 93/14070, WO 96/29315, WO 92/15 567, WO93/20061, WO 93/20062, WO 95/11894, U.S. Pat. No. 5,486,526, WO93/12107, WO 93/12108, WO 95/14007, WO 95/06037, WO 97/29092, EP 680960, WO 96/38141, WO 96/38142, WO 96/40126.

[0007] In the litterature, Plazzi et al., Eur. J. Med. Chem. 1995, 30,881, Clitherow et al., Bioorg. & Med. Chem. Lett. 6 (7), 833-838 (1996)Wolin et al., Bioorg. & Med. Chem. Lett; 8, 2157 (1998) can be citedalso in this respect.

[0008] Nevertheless, such imidazole derivatives may show drawbacks suchas poor blood-brain barrier penetration, interaction with cytochromeP450 proteins and/or some hepatic and ocular toxicities.

[0009] Non-imidazole known neuro-active compounds such as betahistine(J-M. Arrang et al., Eur. J. Pharmacol. 1985, 111: 72-84), phencyclidine(J-M. Arrang et al., Eur. J. Pharmacol. 1988, 157: 31-35), dimaprit (J-CSchwartz et al., Agents Actions 1990, 30: 13-23), clozapine (M. Kathmannet al., Psychopharmacology 1994, 116: 464468), and sesquiterpenes (M.Takigawa et al., JP 06 345 642 (20 Dec. 1994)) were suggested to displayH₃-receptor antagonism but all these compounds have only very lowpotency.

[0010] These compounds were previously known as therapeutic agent beforethe discovery and characterization of the histamine H₃-receptor, inparticular as neuro-active agents for example as neuroleptic (clozapine)or psychotomimetic (Phencyclidine) agent.

[0011] When tested at the H₃-receptor, these compounds were shown todisplay much lower potency than the imidazole-containing compoundsdescribed in patent applications quoted above.

[0012] Attempts at replacing the imidazole ring was generally notsuccessful and no potent H₃-receptor ligands not containing such ringwas reported in the literature up to now.

[0013] These investigations showed the importance of the 4(5)-imidazolemoiety.

[0014] The objective of the invention is to provide new potentH₃-receptor ligands which may reduce the above-mentioned drawbacks.

[0015] The present invention provides new compounds, the structure ofwhich does not contain an imidazole moiety, which are useful ashistamine H₃-receptor ligands.

[0016] The compounds of the invention have the following general formula(A):

[0017] in which:

[0018] W is a residue which imparts antagonistic and/or agonisticactivity at histamine H₃-receptors when attached to an imidazole ring in4(5)-position;

[0019] R¹ and R² may be identical or different and represent eachindependently

[0020] a lower alkyl or cycloalkyl,

[0021] or taken together with the nitrogen atom to which they areattached,

[0022] a saturated nitrogen-containing ring

[0023] with m ranging from 2 to 8, or

[0024] a non-aromatic unsaturated nitrogen-containing ring

[0025] with p and q being from 0 to 3 independently and r being from 0to 4, provided that p and q are not simulteously 0 and 2≦p+q+r≦8,

[0026] R^(a-d) being independently a hydrogen atom or a lower alkyl,cycloalkyl, or carboalkoxy group, or

[0027] a morpholino group, or

[0028] a N-substituted piperazino group:

[0029] with R being a lower alkyl, cycloalkyl, carboalkoxy, aryl,arylalkyl, an alkanoyl or aroyl group.

[0030] The inventors have found, surprisingly, that antagonist and/oragonist compounds can be obtained by substituting a di(alkyl) or(cycloalkyl)amine, or a non-aromatic nitrogen-containing ring —NR¹R² asabove-defined for the imidazole ring, in known antagonist and/or agonistimidazole derivatives.

[0031] It is also believed that antagonist and/or agonist activity canbe foreseen, by equivalence, for compounds according to formula (A)having a W residue of imidazole derivatives which were suggested in theprior art as H₃ antagonists or agonists, and further for those Wresidues which would belong to future imidazole derivatives havingsubstantial H₃ antagonist and/or agonist activity.

[0032] Moreover, the inventors have observed that such non-imidazoleanalogues can provide potent antagonist and/or agonist activity.

[0033] In this regards, they have prepared novel non-imidazolealkylamines analogues of formula (A) corresponding to known imidazolederivatives in particular from the above-mentioned prior art.

[0034] The invention also relates to the addition salts which thecompounds form with pharmaceutically acceptable acids. Thepharmaceutically acceptable salts comprise the nontoxic salt ofinorganic or organic acids. Examples of these salts include thehydrochloride, the hydrobromide or the hydrogen maleate or hydrogenoxalate.

[0035] The present invention also encompasses the hydrates of thecompounds, the hydrated salts of these compounds and the polymorphiccrystalline structures.

[0036] When the compounds can exist in one or a number of isomeric formsaccording to the number of asymmetric centres in the molecule, theinvention relates both to all the optical isomers and to their racemicmodifications and the corresponding diastereoisomers. The separation ofthe diastereoisomers and/or of the optical isomers can be carried outaccording to methods known per se.

[0037] The present invention also encompasses all the possibletautomeric forms of the compounds, whether these tautomers occur inisolated form or in the form of mixtures.

[0038] According to the invention, lower alkyl or cycloalkyl is intendedto mean a linear or branched alkyl group containing from 1 to 6 carbonatoms, or a saturated carbocycle containing 3 to 6 carbon atoms.

[0039] Typically examples of lower alkyl are methyl, ethyl, propyl,isopropyl and butyl groups.

[0040] A preferred group of compounds according to the inventioncomprises those with R¹ and R² representing independently a lower alkylgroup, especially an ethyl group.

[0041] Preferred compounds are also those of formula (A) in which R¹ andR² taken together with the nitrogen atom to which they are attached,form a saturated nitrogen-containing ring:

[0042] especially with m being 4, 5 or 6, optionally substituted with analkyl group (R^(a)), preferably a methyl group.

[0043] The groups R^(a) and R^(b) are identical or different for each(CR^(a)R^(b)) moiety.

[0044] Piperidyl and pyrrolidinyl moieties are especially preferred.

[0045] Another preferred group of compounds comprises compounds (A) inwhich R¹ and R² taken together with the nitrogen atom to which they areattached, form a non-aromatic unsaturated nitrogen-containing ring:

[0046] especially with p, q, and r being independently 1 or 2.

[0047] In this group, more preferred compounds are those with p being 2and q and r each being 1.

[0048] A sub-class in this group comprises compounds with R^(a-d) beingeach a hydrogen atom.

[0049] When NR¹R² is a nitrogen-containing ring i) or ii) asabove-defined, the latter is preferably substituted with one or twolower alkyl group(s), especially a methyl group.

[0050] The position for substitution is preferably selected accordingthe following order:

[0051] meta>para>ortho.

[0052] In this group, for nitrogen-containing ring bearing only onesubstituent, this latter is preferably in meta position with respect tothe nitrogen-atom.

[0053] For nitrogen-containing ring bearing two substituents, meta-metasubstitution is preferred, especially when these two substituents are intrans-relation.

[0054] According to the invention, piperidyl or pyrrolidinyl moietysubstituted in meta or meta-meta position, especially with a methylgroup, give particularly preferred compounds.

[0055] When NR¹R² represents a N-substituted piperazino group, R may bea lower alkyl e.g. methyl.

[0056] Typical examples of group R being an aryl or arylalkyl moiety arephenyl and benzyl.

[0057] R may be also an alkanoyl or aroyl group e.g. acetyl or benzoyl.

[0058] In all the possible groups for R, the alkyl moiety refers to alinear or branched chain containing from 1 to 6 carbon atoms.

[0059] The cycloalkyl group refers to a saturated carbocycle containing3 to 7 carbon atoms.

[0060] When R represents an aryl or arylalkyl group, the aryl moiety isespecially a phenyl group optionally substituted with one or moresubstituents selected from halogen atoms, advantageously selected fromfluorine, chlorine and bromine, or a lower alkyl or cycloalkyl, atrifluoromethyl, aryl, alkoxy, aryloxy, nitro, formyl, alkanoyl, aroyl,arylalkanoyl, amino, carboxamido, cyano, alkyloximino, aryloximino,α-hydroxyalkyl, alkenyl, alkynyl, sulphamido, sulfamoyl, carboxamide,carboalkoxy, arylalkyl or oxime group.

[0061] R may be also an optionally substituted benzoyl, the substituentbeing as defined above with reference to the phenyl group.

[0062] Typical example of —NR¹R² representing a N-substituted piperazinogroup is N-acetylpiperazino.

[0063] According to one aspect, the compounds of the invention have thefollowing general formula (I):

[0064] in which:

[0065] C_(n)H₂n is a linear or branched hydrocarbon chain with n rangingfrom 2 to 8;

[0066] X is an oxygen or sulfur atom;

[0067] n₃ is an integer from 0 to 5;

[0068] R³ represents each independently

[0069] a halogen atom,

[0070] a lower alkyl or cycloalkyl, a trifluoromethyl, aryl, alkoxy,α-alkyloxyalkyl, aryloxy, nitro, formyl, alkanoyl, aroyl, arylalkanoyl,amino, carboxamido, cyano, alkyloximino, alkylalkoximino, aryloximino,a-hydroxyalkyl, alkenyl, alkynyl, sulphamido, sulfamoyl, sulphonamido,carboxamide, carbonylcycloalkyl, alkylcarbonylalkyl, carboalkoxy,arylalkyl or oxime group,

[0071] or taken together with the carbon atoms of the phenyl ring towhich it is fused, a 5 or 6-membered saturated or unsaturated ring or abenzene ring.

[0072] R¹ and R² are as above-defined in formula (A).

[0073] A preferred group of compounds according to the invention is thegroup composed of compounds of formula (I) in which X is an oxygen atom.

[0074] Another preferred group of compounds comprises compounds (I) inwhich —C_(n)H_(2n)— is a linear chain —(CH₂)_(n)— with n being aspreviously defined.

[0075] Preferred compounds are also those with n varying from 3 to 5,and with n being more preferably 3.

[0076] A sub-class of compounds according to the invention comprises thecompounds of formula (I) with n₃ being zero that is those having anunsubstituted phenyl moiety.

[0077] Another group of compounds according to the invention is composedof compounds containing one or more substituents R³ which may beidentical or different. In this group, the compounds having a mono- ordi-substituted (n₃=1 or 2) phenyl moiety are preferred and thosemono-substituted with one group R³ as defined above in para-position areparticularly preferred.

[0078] Among these compounds, (n₃ being 1) R³ is preferably a halogenatom or a cyano, nitro, alkanoyl, alkyloximino or α-hydroxyalkyl group.

[0079] Still more preferred compounds are those with R³ being CN, NO₂,COCH₃, COC₂H₅, H₃C—C═N—OH, H₃C—CH—OH and cycloalkyl-CO likecyclopropyl-CO.

[0080] R³ being a halogen atom may be advantageously selected fromfluorine, chlorine and bromine.

[0081] R³ being an aryl group, may be especially a phenyl group.

[0082] In the other substituents R³, the aryl moiety is advantageously aphenyl moiety.

[0083] R³ being an aryloxy group may be especially a phenoxy group.

[0084] According to the invention, alkanoyl is intended to mean a groupcontaining an alkyl moiety as defined above.

[0085] Typical examples of R³ being an alkanoyl, aroyl or arylalkanoylgroup are acetyl, butyryl and propionyl groups, benzoyl group orphenylacetyl group.

[0086] Typical examples of R³ forming together with the carbon atoms ofthe phenyl ring to which it is fused, a saturated ring leads to5,6,7,8-tetrahydronaphthyl or forming a benzene ring leads to a naphthylmoiety.

[0087] According to the invention, alkenyl or alkynyl group may containadvantageously from 1 to 8 carbon atoms, in particular from 1 to 6carbon atoms and preferably 1 to 4 carbon atoms.

[0088] In carboalkoxy, carboxyamido, carbonylcycloalkyl,alkylcarbonylalkyl, or carboxamide groups, the hydrocarbon chain issaturated, linear or branched and contains an alkyl moiety as definedabove.

[0089] In alkoxy, alkylalkoximino, alkyloximino, α-alkyloxyalkyl,arylalkyl or α-hydroxyalkyl group, the alkyl moiety is as previouslydefined also.

[0090] Particularly preferred compounds are:

[0091] 1-(5-phenoxypentylypiperidine

[0092] 1-(5-phenoxypentylypyrrolidine

[0093] N-methyl-N-(5-phenoxypentyl)-ethylamine

[0094] 1-(5-phenoxypentyl)-morpholine

[0095] N-(5-phenoxypentylyhexamethyleneimine

[0096] N-ethyl-N-(5-phenoxypentyl)-propylamine

[0097] 1-(5-phenoxypentyl)-2-methyl-piperidine

[0098] 1-(5-phenoxypentyl)-4-propyl-piperidine

[0099] 1-(5-phenoxypentyl)-4-methyl-piperidine

[0100] 1-(5-phenoxypentyl)-3-methyl-piperidine

[0101] 1-acetyl-4-(5-phenoxypentylypiperazine

[0102] 1-(5-phenoxypentyl)-3,5-trans-dimethyl-piperidine

[0103] 1-(5-phenoxypentyl)-3,5-cis-dimethyl-piperidine

[0104] 1-(5-phenoxypentyl)-2,6-cis-dimethyl-piperidine

[0105] 4-carboethoxy-1-(5-phenoxypentyl)-piperidine

[0106] 3-carboethoxy-1-(5-phenoxypentyl)-piperidine

[0107] 1-[3-(4-cyclopropylcarbonylphenoxy) propyl]-piperidine

[0108] 1-[3-(4-acetylphenoxy)-2-R-methylpropyl] piperidine

[0109] 1-[3-(4-cyanophenoxy)propyl]-4-methylpiperidine

[0110] 1-[3-(4-cyanophenoxy)propyl]-3-methylpiperidine

[0111] 1-[3-(4-acetylphenoxy)-2-S-methylpropyl] piperidine

[0112] 1-{3-[4-(3-oxobutyl)phenoxy] propyl}piperidine

[0113] 1-[3-(4-cyano-3-fluorophenoxy)propyl] piperidine

[0114] 1-[3-(4-nitrophenoxy)propyl]-3-methylpiperidine

[0115] 1-[3-(4-cyanophenoxy)propyl]-2-methylpiperidine

[0116] 1-[3-(4-nitrophenoxy)propyl]-2-methylpiperidine

[0117] 1-[3-(4-nitrophenoxy)propyl]-4-methylpiperidine

[0118] 1-[3-(4-cyanophenoxy)propyl]-2,6-dimethylpiperidine

[0119] 1-[3-(4-propionylphenoxy)propyl]-3-methylpiperidine

[0120] 1-[3-(4-cyclobutylcarbonylphenoxy)propyl] piperidine

[0121] 1-[3-(4-cyclopentylcarbonylphenoxy) propyl]piperidine

[0122] 1-[3-(4-cyanophenoxy)propyl]-cis-2-methyl-5-ethylpiperidine

[0123] 1-[3-(4-cyanophenoxy)propyl]-trans-2-methyl-5-ethylpiperidine

[0124] 1-[3-(4-cyanophenoxy)propyl]-cis-3,5-dimethylpiperidine

[0125] 1-[3-(4-propionylphenoxy)propyl]-4-methylpiperidine

[0126] 1-[3-(4-propionylphenoxy)propyl]-2-methylpiperidine

[0127] 1-{3-[4-(1-hydroxypropyl)phenoxy]propyl}-3-methylpiperidine

[0128] 1-{3-[4-(1-hydroxypropyl)phenoxy]propyl)-4-methylpiperidine

[0129] 1-[3-(4-propionylphenoxy)propyl]-2-methylpiperidine

[0130] 1-[3-(4-propionylphenoxy)propyl]-4-methylpiperidine methoxime

[0131] 1-[3-(4-cyanophenoxy)propyl]-trans-3,5-dimethylpiperidine

[0132] 1-[3-(4-cyclopropyl carbonyl phenoxy) propyl]-trans-3,5-dimethylpiperidine

[0133] 1-[3-(4-cyclopropyl carbonyl phenoxy)propyl]-cis-3,5-dimethylpiperidine

[0134] 1-[3-(4-carbomethoxyphenoxy)propyl] piperidine

[0135] 1-[3-(4-propenylphenoxy)propyl]-2-methyl piperidine

[0136] 1-[3-(4-propionylphenoxy)propyl]-2-methylpiperidine

[0137] 1-{3-[4-(1-ethoxypropyl)phenoxy]propyl}-2-methyl piperidine

[0138] 1-[3-(4-propionylphenoxy)propyl]-4-methylpiperidine

[0139] 1-[3-(4-bromophenoxy)propyl]piperidine

[0140] 1-[3-(4-nitrophenoxy)propyl]piperidine

[0141] 1-[3-(4-N,N-dimethylsulfonamidophenoxy) propyl]piperidine

[0142] 1-[3-(4-isopropylphenoxy)propyl]piperidine

[0143] 1-[3-(4-sec-butylphenoxy)propyl]piperidine

[0144] 1-[3-(4-propylphenoxy)propyl]piperidine

[0145] 1-[3-(4-ethylphenbxy)propyl]piperidine

[0146] 1-(5-phenoxypentyly-1,2,3,6-trahydropyridine

[0147] 1-[5-(4-nitrophenoxy)-pentyl]-pyrrolidine

[0148] 1-[5-(4-chlorophenoxy)-pentyl]-pyrrolidine

[0149] 1-[5-(4-methoxyphenoxy)-pentyl]-pyrrolidine

[0150] 1-[5-(4-methylphenoxy)-pentyl]-pyrrolidine

[0151] 1-[5-(4-cyanophenoxy)-pentyl]-pyrrolidine

[0152] 1-[5-(2-naphthyloxy)-pentyl]-pyrrolidine

[0153] 1-[5-(1-naphthyloxy)-pentyl]-pyrrolidine

[0154] 1-[5-(3-chlorophenoxy)-pentyl]-pyrrolidine

[0155] 1-[5-(4-phenylphenoxy)-pentyl]-pyrrolidine

[0156] 1-{5-[2-(5,6,7,8-tetrahydronaphthyl)-oxy]-pentyl}-pyrrolidine

[0157] 1-[5-(3-phenylphenoxy)-pentyl]-pyrrolidine

[0158] 1-(5-phenoxypenty)-2,5-dihydropyrrole

[0159] 1-{5-[1-(5,6,7,8-tetrahydronaphthylyoxy]-pentyl}-pyrrolidine

[0160] 1-(4-phenoxybutyl)-pyrrolidine

[0161] 1-(6-phenoxyhexyl)-pyrrolidine

[0162] 1-(5-phenylthiopentyl)-pyrrolidine

[0163] 1-(4-phenylthiobutyl)-pyrrolidine

[0164] 1-(3-phenoxypropyl)-pyrrolidine

[0165] 1-[5-(3-nitrophenoxy)-pentyl]-pyrrolidine

[0166] 1-[5-(4-fluorophenoxy)-pentyl]-pyrrolidine

[0167] 1-[5-(4-nitrophenoxy)-pentyl]-3-methyl-piperidine

[0168] 1-[5-(4-acetylphenoxy)-pentyl]-pyrrolidine

[0169] 1-[5-(4-aminophenoxy)-pentyl]-pyrrolidine

[0170] 1-[5-(3-cyanophenoxy)-pentyl]-pyrrolidine

[0171] N-[3-(4-nitrophenoxy)-propyl]-diethylamine

[0172] N-[3-(4-cyanophenoxy)-propyl]-diethylamine

[0173] 1-[5-(4-benzoylphenoxy)-pentyl]-pyrrolidine

[0174] 1-{5-[4-(phenylacetyl)-phenoxy]-pentyl}-pyrrolidine

[0175] N-[3-(4-acetylphenoxy)-propyl]-diethylamine

[0176] 1-[5-(4-acetamidophenoxy)-pentyl]-pyrrolidine

[0177] 1-[5-(4-phenoxyphenoxy)-pentyl]-pyrrolidine

[0178] 1-[5-(4-N-benzamidophenoxy)-pentyl]-pyrrolidine

[0179] 1-5-[4-(1-hydroxyethyl)-phenoxy]-pentyl}-pyrrolidine

[0180] 1-[5-(4-cyanophenoxy)-pentyl]-diethylamine

[0181] 1-[5-(4-cyanophenoxy)-pentyl)-piperidine

[0182] N-[5-(4-cyanophenoxy)-pentyl]-dimethylamine

[0183] N-[2-(4-cyanophenoxy)-ethyl]-diethylamine

[0184] N-[3-(4-cyanophenoxy)-propyl]-dimethylamine

[0185] N-[4-(4-cyanophenoxy)-butyl]-diethylamine

[0186] N-[5-(4-cyanophenoxy)-pentyl]-dipropylamine

[0187] 1-[3-(4-cyanophenoxy)-propyl]-pyrrolidine

[0188] 1-[3-(4-cyanophenoxy)-propyl]-piperidine

[0189] N-[3-(4-cyanophenoxy)-propyl]-hexamethyleneimine

[0190] N-[6-(4-cyanophenoxy)-hexyl]-diethylamine

[0191] N-[3-(4-cyanophenoxy)-propyl]-dipropylamine

[0192] N-3-[4-(1-hydroxyethyl)-phenoxy]-propyl-diethylamine

[0193] 4-(3-diethylaminopropoxy)-acetophenone-oxime

[0194] 1-[3-(4-acetylphenoxy)-propyl]-piperidine

[0195] 1-[3-(4-acetylphenoxy)-propyl]-3-methyl-piperidine

[0196] 1-[3-(4-acetylphenoxy)-propyl]-3,5-trans-dimethyl-piperidine

[0197] 1-[3-(4-acetylphenoxy)-propyl]-4-methyl-piperidine

[0198] 1-[3-(4-propionylphenoxy)-propyl]-piperidine

[0199] 1-[3-(4-acetylphenoxy)-propyl]-3,5-cis-dimethyl-piperidine

[0200] 1-[3-(4-formylphenoxy)-propyl]-piperidine

[0201] 1-[3-(4-isobutyrylphenoxy)-propyl]-piperidine

[0202] N-[3-(4-propionylphenoxy)-propyl]-diethylamine

[0203] 1-[3-(4-butyrylphenoxy)-propyl]-piperidine

[0204] 1-[3-(4-acetylphenoxy)-propyl]-1,2,3,6-tetrahydropyridine

[0205] More preferred compounds are:

[0206] 1-[5-(4-nitrophenoxy)-pentyl]-pyrrolidine

[0207] N-[3-(4-cyanophenoxy)-propyl]-diethylamine

[0208] N-[3-(4-acetylphenoxy)-propyl]-diethylamine

[0209] 1-{5-[4-(1-hydroxyethyl)-phenoxy]-pentyl}-pyrrolidine

[0210] N-[4-(4-cyanophenoxy)-butyl]-diethylamine

[0211] 1-[3-(4-cyanophenoxy)-propyl]-piperidine

[0212] N-[3-(4-cyanophenoxy)-propyl]-hexamethyleneimine

[0213] N-3-[4-(1-hydroxyethyl)-phenoxy]-propyl-diethylamine

[0214] 4-(3-diethylaminopropoxy)-acetophenone-oxime

[0215] 1-[3-(4-acetylphenoxy)-propyl]-3-methyl-piperidine

[0216] 1-[3-(4-acetylphenoxy)-propyl]-4-methyl-piperidine

[0217] 1-[3-(4-propionylphenoxy)-propyl]-piperidine

[0218] Compounds of formula (I) in which:

[0219] —NR¹R² is a pyrrolidinyl group, C_(n)H_(2n) is a linear chain—(CH₂)_(n)— and n₃ is zero, X being an oxygen atom with n ranging from 3to 5, or X being a sulfur atom with n being 4 or 5;

[0220] —NR¹R² is a piperidinyl group, C_(n)H₂n is a linear chain—(CH₂)_(n)— and X is an oxygen atom, n₃ being zero with n being 2, 5 or8 or n₃ being 1 with R³ being 4-CN and n being 5;

[0221] —NR¹R² is a diethylamine group, X is an oxygen atom, C_(n)H_(2n)is a linear chain —(CH₂)_(n)— and n₃ is 1, R³ being 4-NO₂ or 4-COCH₃with n being 3 or R³ being 4-CN with n being 2 to 4;

[0222] —NR¹R² is a dimethylamine group, X is an oxygen atom, C_(n)H_(2n)is a linear chain —(CH₂)_(n)— and n³ is 1, R³ being 4-CN with n being 3,

[0223] are known in the art.

[0224] A subject of the invention is thus the use of these compounds asligands of the histamine H₃-receptors in particular as H₃-antagonists,agonists and/or partial agonists, in particular to prepare medicamentsacting as ligands for the histamine H₃-receptors in particular asH₃-antagonists and/or agonists, intended for the treatments detailedbelow.

[0225] According to a second aspect, the object of the present inventionis non-imidazole compounds analogous to the compounds disclosed in WO96/29315 and WO 93/14070.

[0226] Thus, a first sub-class of the compounds (A) of the invention isdefined by the compounds having the following general formula (IIa) and(IIb):

[0227] in which

[0228] R¹ and R² are as defined with reference to general formula (A);

[0229] the chain A^(II) represents a saturated or unsaturated, straightor branched hydrocarbon chain containing 1 to 6 carbon atoms, it beingpossible for the saturated hydrocarbon chain to be interrupted by ahetero atom such as a sulphur atom;

[0230] X^(II) represents an oxygen or sulphur atom, —NH—, —NHCO—,—N(alkyl)CO—, —NHCONH—, —NH—CS—NH—, —NHCS—, —O—CO—, —CO—O—, —OCONH—,—OCON(alkyl)-, —OCON(alkene), —OCONH—CO—, —CONH—, —CON(alkyl)-, —SO—,—CO—, —CHOH—, —N(saturated or unsaturated alkyl), —S—C(═NY″)—NH—Y″— withthe Y″ identical or different and as defined previously, or—NR_(II)—C(═NR″_(II))—NR′_(II)—, R_(II) and R′_(II) denoting a hydrogenatom or a lower alkyl radical and R″_(II) a hydrogen atom or anotherpowerful electronegative group, such as a cyano or COY₁ ^(II) group, Y₁^(II) denoting an alkoxy group;

[0231] the chain B^(II) represents an aryl, arylalkyl or arylalkanoylgroup, a straight alkylene chain —(CH₂)_(nII)—, n being an integer whichcan vary between 1 and 5 or a branched alkylene chain containing from 2to 8 carbon atoms, the alkylene chain being optionally interrupted byone or a number of oxygen or sulphur atoms, or a group —(CH₂)_(nII)—O—or —(CH₂)_(nII)—S— where n_(II) is an integer equal to 1 or 2;

[0232] Y^(II) represents a straight or branched alkyl group containing 1to 8 carbon atoms; a cycloalkyl containing 3 to 6 carbon atoms; abicycloalkyl group; a cycloalkenyl group; an aryl group such as anoptionally substituted phenyl group; a 5- or 6-membered heterocyclicradical containing one or two heteroatoms chosen from nitrogen andsulphur atoms, the said heterocyclic radical optionally beingsubstituted; or also a bicyclic radical resulting from the fusion of abenzene ring to a heterocycle as defined above.

[0233] The chain A can be a straight alkylene chain —(CH₂)_(nII)—,n_(II) representing an integer between 1 and 6 carbon atoms, preferablybetween 1 and 4 carbon atoms, or a branched alkylene chain, preferably achain substituted by one or a number of methyl or ethyl radicals.

[0234] The chain A^(II) can also be a straight or branched unsaturatedalkylene chain, and can be, for example, the allyl group.

[0235] When Y^(II) represents a cycloalkyl group, the latter can be, forexample, cyclopentyl, cyclohexyl or a bicycloalkyl group.

[0236] When Y^(II) represents a substituted phenyl group, the phenylgroup can be mono- or polysubstituted, for example, by a halogen, by alower alkyl, for example CH₃, by CF₃, CN, COCH₃, COOR^(II) ₁ or OR^(II)₁, R^(II) ₁ representing a lower alkyl, for example COOCH₃, the NO₂group or the group NR^(II) ₂R^(II) ₃, R^(II) ₂ and R^(II) ₃ representinga hydrogen atom and/or a lower alkyl radical (“lower alkyl” means analkyl radical containing at most 6 carbon atoms).

[0237] When Y^(II) represents a heterocyclic radical, the latter can be,for example, the pyridyl radical, the pyridyl N-oxide radical or thepyrazinyl radical, optionally mono- or polysubstituted by NO₂, CF₃, CH₃,NH₂, a halogen such as Cl, the COOCH₃ group or also the thiazolylradical.

[0238] When Y^(II) represents a polycyclic radical resulting fromcondensed aromatic or heteroaromatic moieties the radical can be, forexample, the benzothiazolyl, quinolinyl, isoquinolinyl radical orrelated moieties.

[0239] A second sub-class of the compounds (A) according to theinvention comprises the compounds having the above-formulae (IIa) and(IIb) in which:

[0240] R¹R² are as defined with reference to general formula (A);

[0241] the chain A^(II) represents an unbranched, branched orunsaturated alkyl group —(CH₂)_(nII)— where n_(II) is an integer whichcan vary between 1 and 8 and preferably between 1 and 4; an unbranchedor branched alkene group comprising from 1 to 8 carbon atoms andpreferably I to 4 carbon atoms; an unbranched or branched alkyne groupcomprising from 1 to 4 carbon atoms;

[0242] the group X^(II) represents —OCONH—; —OCON(alkyl)-;—OCON(alkene)-; —OCO—; —OCSNH—; —CH₂—; —O—; —OCH₂CO—; —S—; —CO—; —CS—;amine; saturated or unsaturated alkyl;

[0243] the chain B^(II) represents an unbranched, branched orunsaturated lower alkyl comprising from 1 to 8 carbon atoms andpreferably 1 to 5 carbon atoms; —(CH₂)_(nII)(hetero atom)- where thehetero atom is preferably a sulphur or oxygen atom; nil being an integerwhich can vary between 1 and 5, preferably between 1 and 4;

[0244] the group Y^(II) represents a phenyl group, unsubstituted ormono- or polysubstituted with one or more identical or differentsubstituents selected from halogen atoms, OCF₃, CHO, CF₃, SO₂N(alkyl)₂such as SO₂N(CH₃)₂, NO₂, S(alkyl), S(aryl), SCH₂(phenyl), an unbranchedor branched alkene, an unbranched or branched alkyne optionallysubstituted with a trialkylsilyl radical, —O(alkyl), —O(aryl), —CH₂CN, aketone, an aldehyde, a sulphone, an acetal, an alcohol, a lower alkyl,—CH═CH—CHO, —C(alkyl)=N—OH, —C(alkyl)=N—O(alkyl) and other ketoderivatives, —CH═NOH, —CH═NO(alkyl), and other aldehyde derivatives,—C(alkyl)=NH—NH—CONH₂, an O-phenyl or —OCH₂(phenyl) group,—C(cycloalkyl)=NOH, —C(cycloalkyl)=N—O(alkyl), an optionally substitutedheterocycle; a heterocycle comprising a sulphur hetero atom; acycloalkyl; a bicyclic group and preferably a norbornyl group; a phenylring fused to a heterocycle comprising a nitrogen hetero atom or to acarbocycle or a heterocycle bearing a keto function; an unbranched orbranched lower alkyl comprising from 1 to 8 carbon atoms; an unbranchedor branched alkyne comprising from 1 to 8 carbon atoms and preferably 1to 5 carbon atoms; a linear or branched alkyl mono- or polysubstitutedwith phenyl groups which are either unsubstituted or mono- orpolysubstituted; a phenyl alkyl ketone in which the alkyl group isbranched or unbranched or cyclic; a substituted or unsubstitutedbenzophenone; a substituted or unsubstituted, unbranched or branched orcyclic phenyl alcohol; an unbranched or branched alkene; a piperidylgroup; a phenylcycloalkyl group; a polycyclic group, in particular afluorenyl group, a naphthyl or polyhydronaphthyl group or an indanylgroup; a phenol group; a ketone or keto derivative; a diphenyl group; aphenoxyphenyl group; a benzyloxyphenyl group.

[0245] According to the invention, group X^(II) representing an amine isunderstood to mean a secondary or tertiary amine.

[0246] The alkyl, alkene, alkyne, keto, aldehyde, cycloalkyl, S-alkyl,O-alkyl, phenyl alcohol and phenyl-cycloalkyl groups mentioned above aswell as in the remainder of the description and the claims of thepresent patent comprise from 1 to 8 carbon atoms, and preferably 1 to 5.

[0247] Likewise, keto derivatives are understood to mean any oxime,alkyloxime, hydrazone, acetal, aminal, ketal, thione, carbazone orsemicarbazone group and the thio analogues of these derivatives.

[0248] Likewise, by mono- or polysubstituted phenyl and/or benzophenonegroups, it is understood to mean that these groups are substituted withone or more identical or different substituents selected from halogenatoms, OCF₃, CHO, CF₃, SO₂N(alkyl)₂, SO₂N(CH₃)₂, NO₂, S(alkyl), S(aryl),SCH₂(phenyl), an unbranched or branched alkene, an unbranched orbranched alkyne optionally substituted with a trialkylsilyl radical,—O(alkyl), —O(aryl), —CH₂CN, a ketone, an aldehyde, a sulphone, anacetal, an alcohol, a lower alkyl, —CH═CH—CHO, —C(alkyl)=N—OH,—C(alkyl)=N—O(alkyl) an other keto derivatives, —CH═NOH, —CH═NO(alkyl),and other aldehyde derivatives, —C(alkyl)=NH—NH—CONH₂, an O-phenyl or—OCH₂(phenyl) group, —C(cycloalkyl)=NOH, —C(cycloalkyl)=N—O(alkyl), anoptionally substituted heterocycle.

[0249] The keto substituent is preferably selected from a linear- orbranched-chain aliphatic ketone, it being possible for the said chain tocomprise from 1 to 8 carbon atoms and optionally to bear a hydroxylgroup, a cycloalkyl ketone, an aryl alkyl ketone or aryl alkenyl ketonein which the aryl group is unsubstituted or mono- or polysubstituted, ora heteroaryl ketone in which the heteroaryl unit is preferablymonocyclic.

[0250] The acetal substituent preferably consists of an aliphatic acetalcomprising from 1 to 8 carbon atoms and optionally bearing a hydroxylradical.

[0251] Group Y^(II) representing a ketone is understood to mean, inparticular, a ketone substituted with an alkyl or aryl group, it beingpossible for these groups to be substituted or unsubstituted.

[0252] As regards the heterocycles, these comprise from 1 to 3 heteroatoms, preferably sulphur, oxygen or nitrogen atoms.

[0253] The heterocycle substituent is preferably selected from anoxadiazole or an imidazole.

[0254] Preferred compounds (IIa) and (IIb) are those in which X^(II) isselected from —O—, —NH—, —CH₂—, —OCONH—, —NHCO—, —NHCONH—. X^(II)represents more preferably an oxygen atom.

[0255] Preferred compounds (IIa) and (IIb) are also those in whichY^(II) is selected from a linear or branched alkyl group as abovedefined; a cycloalkyl group as above-defined, in particular cyclopentylor cyclohexyl group; a phenyl group unsubstituted or mono-substituted,preferred substituent being halogen atom, in particular chorine; aheterocyclic radical, in particular pyridyl N-oxide or pyrazinylradicals; a bicyclic radical such as a benzothiazolyl radical.

[0256] Y^(II) is preferably a phenyl group at least mono-substitutedwith —CHO, a ketone, an aldehyde, —CH═CH—CHO, —C(alkyl)=N—OH,—C(alkyl)=N—O(alkyl) and other keto derivatives, —CH═N—OH, —CH═NO(alkyl)and other aldehyde derivatives, —C(cycloalkyl)=NOH,—C(cycloalkyl)=N—O(alkyl).

[0257] According to the invention, Y^(II) represents especially a phenylgroup at least mono-substituted with a keto-substituent or anoxime-substituent, or an halogen atom.

[0258] Particularly preferred keto-substituent is cycloalkylketone.

[0259] Other preferred compounds are those wherein Y^(II) represents aphenyl group fused to a carbocycle bearing a keto-function.

[0260] Yet other preferred Y^(II) are phenylalkyl ketone in which thealkyl group is branched or unbranched or cyclic; an optionallysubstituted benzophenone, a ketone.

[0261] Particularly preferred group Y^(II) are a phenyl groupunsubstituted or mono-substituted as above-defined.

[0262] The chain A^(II) is preferably a chain —(CH₂)_(n) ^(II)— withn_(II) varying from 1 to 6, preferably from 1 to 4. The chain A^(II)represents especially —(CH₂)₃—.

[0263] Preferred chain B^(II) is —(CH₂)₂— or —(CH₂)₃—.

[0264] Among compounds (IIa) and (IIb), particularly preferred compoundsare those in which X^(II) is an oxygen atom, the chain A^(II) represents—(CH₂)₃— and, for compounds of formula (IIa), the chain B^(II)represents —(CH₂)₃— also.

[0265] In this group, Y^(II) is preferably an aryl group.

[0266] Preferred group R¹ and R² are as above-defined with reference toformula (A).

[0267] Examples of compounds (IIa) and (IIb) are:

[0268] 3,3-Dimethylbutyl 3-piperidinopropyl ether

[0269] 3-Phenylpropyl 3-piperidinopropyl ether

[0270] 3-(4-Chlorophenyl)propyl 3-piperidinopropyl ether

[0271] 2-Benzothiazolyl 3-piperidinopropyl ether

[0272] 3-Phenylpropyl 3-(4-methylpiperidino)propyl ether

[0273] 3-Phenylpropyl 3-(3,5-cis-dimethylpiperidino)propyl ether

[0274] 3-Phenylpropyl 3-(3,5-trans-dimethylpiperidino)propyl ether

[0275] 3-Phenylpropyl 3-(3-methylpiperidino)propyl ether

[0276] 3-Phenylpropyl 3-pyrrolidinopropyl ether

[0277] 3-(4-Chlorophenyl)propyl 3-(4-methylpiperidino)propyl ether

[0278] 3-(4-Chloro phenyl) propyl 3-(3,5-cis-dimethyl piperidino) propylether

[0279] 3-(4-Chloro phenyl) propyl 3-(3,5-trans-dimethyl piperidino)propyl ether

[0280] 3-Phenylpropyl 3-(N,N-diethylamino)propyl ether

[0281] N-Phenyl-3-piperidinopropyl carbamate

[0282] N-Pentyl-3-piperidinopropyl carbamate

[0283] (S)-(+)-N-[2-(3,3-Dimethyl)butyl]-3-piperidinopropyl carbamate

[0284] 3-Cyclopentyl-N-(3-(1-pyrrolidinyl)propyl)propanamide

[0285] N-Cyclohexyl-N′-(1-pyrrolidinyl-3-propyl)urea

[0286] 2-((2-Piperidinoethyl)amino)benzothiazole

[0287] 5-Piperidinopentylamine

[0288] 2-Nitro-5-(6-piperidinohexyl)pyridine

[0289] 3-Nitro-2-(6-piperidinohexylamino)pyridine

[0290] 2-(6-Piperidinohexylamino)pyrimidine

[0291] N-(6-Phenylhexyl)piperidine

[0292] N-(3-(N,N-Diethylamino)propyl)N′-phenylurea

[0293] N-Cyclohexylmethyl-N′-(3-piperidinopropyl)guanidine

[0294] According to a third aspect, the object of the present inventionis non-imidazole compounds analogous to the compounds disclosed in EP197 840.

[0295] Thus, a sub-class of compounds (A) according to the inventioncomprises compounds having the following formula (III)

[0296] in which:

[0297] NR¹R² is either in 3-position or in 4-position on the piperidylmoiety, R¹ and R² being as defined with reference to formula (A);

[0298] R₂ ^(III) denotes a linear or branched alkyl group having 1 to 6carbon atoms; a piperonyl group, a 3-(1-benzimidazolonyl)propyl group; agroup of formula

[0299] in which n_(III) is 0, 1, 2 or 3, X^(III) is a single bond oralternatively —O—, —S—, —NH—, —CO—, —CH═CH— or

[0300] and R₃ ^(III) is H, CH₃, halogen, CN, CF₃ or an acyl group —COR₄^(III), R₄ ^(III) being a linear or branched alkyl group having 1 to 6carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a phenylgroup which can bear a CH₃ or F substituent; or alternatively a group offormula

[0301] in which Z^(III) denotes an O or S atom or a divalent group NH,N—CH₃ or N—CN and R₅ ^(III) denotes a linear or branched alkyl grouphaving 1 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbonatoms which can bear a phenyl substituent, a (C₃-C₆ cycloalkyl) (linearor branched, C₁-C₃ alkyl) group, a phenyl group which can bear a CH₃,halogen or CF₃ substituent, a phenyl(linear or branched, C₁-C₃ alkyl)group or a naphthyl, adamantyl or p-toluenesulphonyl group.

[0302] Preferred compounds (III) are those with R^(III) representing thegroup

[0303] Z^(III) and R^(III) ₅ being as above-defined and Z^(III) isespecially O, S or NH.

[0304] Preferred group R^(III) ₅ is a (C₃-C₆)cycloalkyl group.

[0305] Preferred R¹ and R² groups are as above-described in formula (A).

[0306] An example of such compound (III) isN′-Cyclohexylthiocarbamoyl-N-1,4′-bipiperidine (compound 123).

[0307] According to a fourth aspect, a sub-class of compounds (A)includes the compounds which have the following formula (IV), analogousto compounds disclosed in EP 494 010:

[0308] in which

[0309] R¹ and R² are as defined with reference to general formula (A);

[0310] R^(IV) represents a hydrogen atom or a group COR₃ ^(IV), in whichR₃ ^(IV) represents

[0311] (a) a linear or branched aliphatic group containing 1 to 11, andin particular 1 to 9, carbon atoms;

[0312] (b) a cyclane ring-system such as cyclopropane,phenylcyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, norbornane, adamantane, noradamantane,chlorooxonorbornane, chloroethylenedioxynorbomane,bromoethylenedioxynorbornane and the anhydride group ofhydroxycarboxy-1,2,2-trimethylcyclopentanecarboxylic acid;

[0313] (c) a benzene ring, unsubstituted or substituted at thepara-position with a linear or branched aliphatic group containing 3 to5 carbon atoms, as well as with a halogen;

[0314] (d) a group (CH₂)_(mIV)R₄ ^(IV) in which m_(IV) is a numberbetween 1 and 10, and R₄ ^(IV) represents a cyclane ring system such ascyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cycloheptane, norbomane, noradamantane, adamantane and6,6-dimethylbicyclo[3.1.1] heptene; a benzene ring, unsubstituted ormonosubstituted with a fluorine atom, a chlorine atom, a methyl group ora methoxy group; a thiophene ring grafted via its ring-position 2 or itsring-position 3; a carboxylic acid ester group COOR₅ ^(IV), in which R₅^(IV) is a cyclane ring-system such as cyclopropane, cyclobutane,cyclopentane, cyclohexane or norbornane; a carboxylic acid amide groupof structure CONHR₆ ^(IV), in which R₆ ^(IV) represents a cyclanering-system such as cyclopropane, cyclobutane, cyclopentane, cyclohexaneor norbomane; a carboxylic acid amide group of structure

[0315] in which the group

[0316] represents pyrrolidine, piperidine or 2,6-dimethylmorpholine; oran ether group —O—R₇ ^(IV), it being possible for R₇ ^(IV) to be abenzene ring, unsubstituted or monosubstituted with a chlorine orfluorine atom or disubstituted with a chlorine atom and with a methylgroup;

[0317] (e) a group —CH═CHR₈ ^(IV), in which R₈ ^(IV) represents acyclane ring-system such as cyclopropane, cyclobutane, cyclopentane,cyclohexane, norbomane or norbomene;

[0318] (f) a secondary amine group —NH(CH₂)_(nIV)R₉ ^(IV), in whichn_(IV) is a number between 1 and 5 and R₉ ^(IV) constitutes a cyclanering-system such as cyclopropane, cyclobutane, cyclopentane, cyclohexaneor norbomane, or a benzene ring, unsubstituted, mono-substituted with afluorine or chlorine atom or with a methoxy group or trisubstituted withmethoxy groups;

[0319] R^(IV) also represents a hydroxyalkenyl group

[0320] in which p_(IV) is a number between 2 and 9 and R₁₀ ^(IV),represents a benzene ring or a phenoxy group; as well as a group

CSNH(CH₃)_(nIV)R₉ ^(IV)

[0321] in which n_(IV) is a number between 1 and 5 and R₉ ^(IV) has themeaning stated above.

[0322] Preferred compounds (IV) are those in which R^(IV) represents thegroup COR₃ ^(IV), R₃ ^(IV) representing especially an aliphatic groupa).

[0323] An example of compound (IV) is N-Heptanoyl-1,4′-bipiperidine or1-(5-Cyclohexylpentanoyl)-1,4-bipiperidine.

[0324] According to a fifth aspect, the invention is relative tonon-imidazole compounds analogous to those disclosed by Plazzi et al.(Eur. J. Med. Chem. 1995, 30, 881).

[0325] Thus, another sub-class of compounds (A) comprises compoundshaving the following formula (V):

[0326] in which

[0327] R¹ and R² are as defined with reference to formula (A) in claim1;

[0328] q^(V) is 2 to 5

[0329] Z^(V) represents NH, O or S

[0330] X_(v) represents a heterocycle, optionally condensed, containingone or more heteroatoms like nitrogen, oxygen or sulfur, unsubstitutedor substituted by one or more groups like aryl, lower alkyl and halogen.

[0331] Preferred compounds are those with X^(V) being an heterocyclelike:

[0332] with Y^(V) representing an hydrogen atom, an halogen or a loweralkyl.

[0333] Examples of compounds (V) are:

[0334] 2-((2-Piperidinoethyl)amino)benzothiazole

[0335] 2-(6-Piperidinohexylamino)benzothiazole

[0336] 4-(6-Piperidinohexylamino)quinoline

[0337] 2-Methyl 4-(3-piperidinopropylamino)quinoline

[0338] 2-Methyl 4-(6-piperidinohexylamino)quinoline

[0339] 7-Chloro-4-(3-piperidinopropylamino)quinoline

[0340] 7-Chloro-4-(4-piperidinobutylamino)quinoline

[0341] 7-Chloro-4-(8-piperidinooctylamino)quinoline

[0342] 7-Chloro-4-(10-piperidinodecylamino)quinoline

[0343] 7-Chloro-4-(12-piperidinododecylamino)quinoline

[0344] 7-Chloro-4-(4-(3-piperidinopropoxy)phenylamino)quinoline

[0345] 7-Chloro-4-(2-(4-(3-piperidinopropoxy) phenyl) ethylamino)quinoline

[0346] According to a sixth aspect, the present invention concernsnon-imidazole compounds which are analogous to those disclosed in WO95/14007.

[0347] Thus, another subclass of compounds (A) includes the compoundshaving the following formula (VI):

[0348] wherein:

[0349] A^(VI) is selected from —O—CO—NR¹ _(VI)—, —O—CO—, —NR¹ _(VI)—CO—,—NR¹ _(VI)—, —NR¹ _(VI)—CO—, —NR¹ _(VI)—, —O—, —CO—NR¹ _(VI)—, —CO—O—,and —C(═NR¹ _(VI))—NR¹ _(VI)—;

[0350] the groups R¹ _(VI), which may be the same or different whenthere are two or three such groups in the molecule of formula VI, areselected from hydrogen, and lower alkyl, aryl, cycloalkyl, heterocyclicand heterocyclyl-alkyl groups, and groups of the formula—(CH₂)_(yVI)-G^(VI), where G^(VI) is selected from CO₂R³ _(VI), COR³_(VI), CONR³ _(VI)R⁴ _(VI), OR³ _(VI), SR³ _(VI), NR³ _(VI)R⁴ _(VI),heteroaryl and phenyl, which phenyl is optionally substituted byhalogen, lower alkoxy or polyhaloloweralkyl, and y_(VI) is an integerfrom 1 to 3;

[0351] R² _(VI) is selected from hydrogen and halogen atoms, and alkyl,alkenyl, alkynyl and trifluoromethyl groups, and groups of the formulaOR³ _(VI), SR³ _(VI) and NR³ _(VI)R⁴ _(VI);

[0352] R³ _(VI) and R⁴ _(VI) are independently selected from hydrogen,and lower alkyl and cycloalkyl groups, or R³ _(VI) and R⁴ _(VI) togetherwith the intervening nitrogen atom can form a saturated ring containing4 to 6 carbon atoms that can be substituted with one or two lower alkylgroups;

[0353] the group —(CH₂)_(nVI)A^(VI)R¹ _(VI) is at the 3- or 4-position,and the group R² _(VI) is at any free position;

[0354] m_(VI) is an integer from 1 to 3;

[0355] and n_(VI) is 0 or an integer from 1 to 3.

[0356] When used herein, the following terms have the given meanings:

[0357] lower alkyl (including the alkyl portions of loweralkoxy)—represents a straight or branched, saturated hydrocarbon chainhaving from 1 to 6 carbon atoms, preferably from 1 to 4;

[0358] lower alkenyl (in R² _(VI))—represents a straight or branchedaliphatic hydrocarbon radical having at least one carbon-to-carbondouble bond (preferably in conjugation with the benzene ring that thegroup R² substitutes) and having from 2 to 6 carbon atoms;

[0359] lower alkynyl (in R² _(VI))—represents a straight or branchedaliphatic hydrocarbon radical having at least one carbon-to-carbontriple bond (preferably in conjugation with the benzene ring that thegroup R² substitutes) and having from 2 to 6 carbon atoms;

[0360] aryl—represents a carbocyclic group having from 6 to 14 carbonatoms and having at least one benzenoid ring, with all availablesubstitutable aromatic carbon atoms of the carbocyclic group beingintended as possible points of attachment, said carbocyclic group beingoptionally substituted with 1 to 3 Y_(VI) groups, each independentlyselected from halo, alkyl, hydroxy, loweralkyoxy, phenoxy, amino,loweralkylamino, diloweralkylamino, and polyhaloloweralkyl. Preferredaryl groups include 1-naphthyl, 2-naphthyl and indanyl, and especiallyphenyl and substituted phenyl;

[0361] cycloalkyl—represents a saturated carbocyclic ring having from 3to 8 carbon atoms, preferably 5 or 6;

[0362] halogen—represents fluorine, chlorine, bromine and iodine;

[0363] heterocyclic—represents, in addition to the heteroaryl groupsdefined below, saturated and unsaturated cyclic organic groups having atleast one O, S and/or N atom interrupting a carbocyclic ring structurethat consists of one ring or two fused rings, wherein each ring is 5-,6- or 7-membered and may or may not have double bonds that lackdelocalized pi electrons, which ring structure has from 2 to 8,preferably from 3 to 6 carbon atoms; e.g., 2- or 3-piperidinyl, 2- or3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3-thiomorpholinyl;

[0364] heteroaryl—represents a cyclic organic group having at least oneO, S and/or N atom interrupting a carbocyclic ring structure and havinga sufficient number of delocalized pi electrons to provide aromaticcharacter, with the aromatic heterocyclic group having from 2 to 14,preferably 4 or 5 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or

[0365] 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, or 3- or 4-pyridazinyl,etc.

[0366] Preferred heteroaryl groups are 2-, 3- and 4-pyridyl;

[0367] heterocyclyl-alkyl—represents a heterocyclic group defined abovesubstituting an alkyl group; e.g., 2-(3-piperidinyl)-ethyl,(2-piperazinyl)-methyl, 3-(2-morpholinyl)-propyl,(3-thiomorpholinyl)-methyl, 2-(4-pyridyl)-ethyl, (3-pyridyl)-methyl, or(2-thienyl)-methyl.

[0368] Preferably, A^(VI) is —CH₂—NR¹ _(VI)— or especially —C(═NH)NR¹_(VI)— preferred compounds include those wherein m_(VI) is 1 or 2, andn_(VI) is 0, 1 or 2.

[0369] Other preferred values of A include —O—CO—NR¹ _(VI)—, —O—, and—CO—O—. In all these compounds, the groups R¹ _(VI) are as definedabove, and the side chain is preferably at the 4-position. In compoundsof formula VI, one group R¹ _(VI) is preferably selected from hydrogen,2-phenylethyl, 4-chlorophenylmethyl, 4-methoxyphenylmethyl,4-trifluoromethylphenylmethyl and 4-pyridylmethyl, but is especially4-chlorophenylmethyl; any other group R¹ _(VI) that is present ispreferably a hydrogen atom or a methyl group.

[0370] Particularly preferred compounds are those wherein n_(VI) andm_(VI) are each 1, and A^(VI) represents an oxygen atom.

[0371] R¹ _(VI) is preferably an aryl or —(CH₂)_(yVI)-G^(VI) with G^(VI)being a phenyl.

[0372] R¹ and R² are preferably selected as specified with reference toformula (A).

[0373] Another sub-class of compounds (A) comprises compounds of formula(VI) wherein R¹ _(VI) represents an aryl group, especially a phenyloptionally substituted with a keto substituent, R² _(VI), n_(VI), m_(VI)and A^(VI) having the above-meaning.

[0374] The keto substituent is as above-defined in Y^(II) with referenceto compounds (IIa) and (IIb).

[0375] Preferred compounds are those with n_(VI) and m_(VI) being each 1and A^(VI) being an oxygen atom.

[0376] Examples of compounds VI are:

[0377] α-(Acetylphenoxy)-α′-piperidino p-xylol

[0378] α-(4-Acetylphenoxy)-α′-(1-pyrrolidinyl)p-xylol

[0379] α-(3-Phenylpropoxy)-α′-pipenidino p-xylol

[0380] α-(4-Acetylphenoxy-α′-(4-methylpiperidino)p-xylol

[0381] α-(4-Acetylphenoxy)-α′-(3,5-cis-dimethylpiperidino)p-xylol

[0382] α-(4-Acetylphenoxy)-α′-(3,5-trans-dimethylpiperidino)p-xylol

[0383] α-(4-Acetylphenoxy)-α′-(2-methylpyrrolidino)p-xylol

[0384] α-(4-Cyclopropylcarbonylphenoxy)-α′-piperidino-p-xylol

[0385] α-(4-Cyclopropylcarbonylphenoxy)-α′-(4-methylpiperidino)p-xylol

[0386] α-(4-Cyclopropylcarbonylphenoxy)-α′-pyrrolidino-p-xylol

[0387] N-(4-Chlorobenzyl)-2-(4-piperidino methyl) phenyl) ethanamidine

[0388] According to a seventh aspect, the present invention is directedto another sub-class of compounds (A) including non-imidazole compoundshaving the following formula (VII) which are analogous to compoundsdisclosed in Clitherow et al. (Bioorg. & Med. Chem. Lett., 6 (7), 833,1996):

[0389] in which

[0390] R¹ and R² are as defined in reference to formula (A);

[0391] X^(VII), Y^(VII) and Z^(VII) are identical or different andrepresent O, N or S;

[0392] n_(VII) is varying from 1 to 3;

[0393] m_(VII) is 1 or 2.

[0394] n_(VII) is preferably 2 or 3, especially 2 and m_(VI) ispreferably 1.

[0395] Preferred compounds are those with X^(VII) being 0 and Y^(VII)and Z^(VII) each being N to represent a 1, 2, 4-oxadiazolyl group.

[0396] An illustrative compound is given in example 130.

[0397] According to a eighth aspect, the present invention is directedto another sub-class of compounds (A) including the non-imidazolecompounds having the following formula (VIII), which are analogous tothose disclosed in WO 95/06037:

[0398] wherein R¹ and R² are as defined with reference to formula (A)and wherein

[0399] A^(VIII) is

[0400] 1) a group of the formula (CH₂)_(mVIII), wherein m_(VIII)=0-9; or

[0401] 2) a group of the formula:

[0402] wherein R⁵ _(VIII) represents hydrogen, (C₁-C₃)alkyl-,aryl(C₁-C₃)alkyl-, aryl-, wherein aryl may optionally be substituted,hydroxyl-, (C₁-C₃)alkoxy-, halogen, amino-, cyano- or nitro; and R⁶_(VIII) represents hydrogen, (C₁-C₃)alkyl-, aryl(C₁-C₃)alkyl-, or aryl-,wherein aryl may optionally be substituted; or

[0403] 3) a group of the formula:

[0404] wherein R⁵ _(VIII) and R⁶ _(VIII) are as defined above; or

[0405] 4) a group of the formula:

[0406] if B^(VIII) is a group of the formula:

[0407] such that A^(VIII) and B^(VIII) together form a group of theformula:

[0408] wherein R⁶ _(VIII) is as defined above; or

[0409] 5) a group of the formula:

[0410] wherein R⁶ _(VIII) is as defined above; or

[0411] 6) a group of the formula:

[0412] if B^(VIII) is a group of the formula:

[0413] such that A^(VIII) and B^(VIII) together form a group of theformula:

[0414] wherein R⁶ _(VIII) is as defined above; or

[0415] 7) a group of the formula:

—(CH₂)_(x) _(VIII) —S—(CH₂)_(y) _(VIII) —

[0416] wherein x_(VIII)+Y_(VIII)=m_(VIII)−1;

[0417] B_(VIII) is

[0418] 1) a group of the formula:

[0419] wherein R⁵ _(VIII) is as defined above; or

[0420] 2) a group of the formula:

[0421] if A is a group of one of the formulas:

[0422] such that A and B together form a group of one of the formulas:

[0423] wherein R⁶ _(VIII) is as defined above; or

[0424] 3) a group of the formula:

[0425] if X^(VIII) is a group of the formula:

[0426] such that B^(VIII) and X^(VIII) together form a group of theformula

[0427] wherein p_(VIII)=1-3; or

[0428] X^(VIII) is

[0429] 1) a group of the formula (CH₂)_(nVIII) wherein n_(VIII)=2-4; or

[0430] 2) a group of the formula:

[0431] if B^(VIII) is a group of the formula:

[0432] such that X^(VIII) and B^(VIII) together form a group of theformula:

[0433] wherein P_(VIII)=1-3; or

[0434] 3) two hydrogens (one on the carbon and one on the nitrogen); or

[0435] 4) one hydrogen on the carbon atom and one R⁷ _(VIII) group onthe nitrogen atom,

[0436] wherein R⁷ _(VIII) represents hydrogen, (C₁-C₁₀)alkyl-, aryl(C₁-C₁₀)alkyl-, or aryl, wherein aryl may optionally be substituted;

[0437] Y^(VIII) is a group of the formula (CH₂)_(kVIII), whereink_(VIII)=0-2;

[0438] R⁴ _(VIII) represents hydrogen, (C₁-C₁₀)alkyl-,(C₁-C₃)alkyl-sulfonamide-, aryl(C₁-C₁₀)alkyl-, aryl, wherein aryl mayoptionally be substituted;

[0439] or a group of the formula:

[0440] or a group of the formula:

[0441] wherein X^(VIII) represents O, S, or NH,

[0442] R⁷ _(VIII) is as defined as above;

[0443] R⁸ _(VIII) represents (C₁-C₁₀)alkyl-, aryl(C₁-C₁₀)alkyl- or aryl,

[0444] wherein aryl may optionally be substituted and wherein aryl isphenyl, substituted phenyl, naphtyl, substituted naphtyl, pyridyl.

[0445] The present invention comprises both linear and ringstructuredcompounds.

[0446] The linear compounds have for example one of the formulas

[0447] Preferred R¹and R² groups are as defined with reference toformula (A).

[0448] A compound (VIII) is described in examples 132 and 169.

[0449] According to a ninth aspect, the invention is relative to asub-class of compounds (A) consisting of compounds having the followingformula (IX) which are analogous to those described in WO 97/29092:

[0450] wherein:

[0451] R¹ and R² are as defined with reference to formula (A)

[0452] R¹ _(IX) is C₄ to C₂₀ hydrocarbyl (in which one or more hydrogenatoms may be replaced by halogen, and up to four carbon atoms [andespecially from 0 to 3 carbon atoms] may be replaced by oxygen, nitrogenor sulphur atoms, provided that R¹ _(IX) does not contain an—O—O-group),

[0453] R² _(IX) identical or different, are H or C₁ to C₁₅ hydrocarbyl(in which one or more hydrogen atoms may be replaced by halogen, and upto three carbon atoms may be replaced by oxygen, nitrogen or sulphuratoms, provided that R² _(IX) does not contain an —O—O-group),

[0454] m_(IX) is from 1 to 15 (preferably 1 to 10, more preferably 3 to10, eg. 4 to 9)

[0455] each X^(IX) group is independently

[0456] or one X^(IX) group is —N(R⁴ _(IX))—, —O— or —S— (provided thatthis X^(IX) group is not adjacent the —NR² _(IX)— group) and theremaining X^(IX) groups are independently

[0457] R³ _(IX) is H, C₁ to C₆ alkyl, C₂ to C₆ alkenyl, —CO₂R⁵ _(IX),—CON(R⁵ _(IX))₂, —CR⁵ _(IX2)OR⁶ _(IX) or —OR⁵ _(IX) (in which R⁵ _(IX)and R⁶ _(IX) are H or C₁ to C₃ alkyl), and R⁴ _(IX) is H or C₁ to C₆alkyl.

[0458] The term “hydrocarbyl”, as used herein, refers to monovalentgroups consisting of carbon and hydrogen. Hydrocarbyl groups thusinclude alkyl, alkenyl, and alkynyl groups (in both straight andbranched chain forms), cycloalkyl (including polycycloalkyl),cycloalkenyl, and aryl groups, and combinations of the foregoing, suchas alkylaryl, alkenylaryl, alkynylaryl, cycloalkylaryl, andcycloalkenylaryl groups.

[0459] A “carbocyclic” group, as the term is used herein, comprises oneor more closed chains or rings, which consist entirely of carbon atoms.Included in such groups are alicyclic groups (such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and adamantyl), groups containingboth alkyl and cycloalkyl moieties (such as adamantanemethyl), andaromatic groups (such as phenyl, naphthyl, indanyl, fluorenyl,(1,2,3,4)-tetrahydronaphthyl, indenyl and isoindenyl).

[0460] The term “aryl” is used herein to refer to aromatic carbocyclicgroups, including those mentioned above.

[0461] When reference is made herein to a substituted carbocyclic group(such as substituted phenyl), or a substituted heterocyclic group, thesubstituents are preferably from 1 to 3 in number and selected from C₁to C₆ alkyl, C₁ to C₆ alkoxy, C₁ to C₆ alkylthio, carboxy, C₁ to C₆carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C₁ to C₆ alkylamino,di(C₁ to C₆ alkyl)amino, aryl, C₁ to C₆ alkylaryl, halo, sulphamoyl andcyano.

[0462] The term “halogen”, as used herein, refers to any of fluorine,chlorine, bromine and iodine.

[0463] Preferably, R² _(IX) is selected from H, C₁ to C₆ alkyl, C₁ to C₆cycloalkyl, C₁ to C₆ hydroxyalkyl, C₁ to C₆ alkylhydroxyalkyl, aryl C₁to C₆ alkyl and substituted aryl C₁ to C₆ alkyl. For example, R² _(IX)may be H or C₁ to C₃ alkyl.

[0464] In certain embodiments, —X^(IX) _(mIX—) is a C₁ to C₈ alkylenegroup, e.g. a butylene group.

[0465] Included in the definition of R¹ _(IX) are aryl-containing groups(such as phenyl, substituted phenyl, naphthyl and substituted naphthyl),and (cycloalkyl)alkyl groups (such as cyclohexylpropyl andadamantylpropyl).

[0466] Preferably, R¹ _(IX) is a group of the formula

[0467] wherein

[0468] p_(IX) is 0 or 1,

[0469] R¹¹ _(IX) is H or C₁ to C₃ alkyl,

[0470] q_(IX) is from 0 to 4,

[0471] R¹² _(IX) is a carboxyclic, substituted carbocyclic, heterocyclicor substituted heterocyclic group, and

[0472] R¹³ _(IX) is independently selected from H, C₁ to C₆ alkyl, C₁ toC₆ cycloalkyl, C₁ to C₆ hydroxyalkyl, C₁ to C₆ alkylhydroxyalkyl, arylC₁ to C₆ alkyl and substituted aryl C₁ to C₆ alkyl.

[0473] Preferably, R¹³ _(IX) is hydrogen.

[0474] Compounds (IX) wherein R¹ _(IX) is a group —NH—CH₂—Ph where Phrepresents an optionally substituted phenyl, are preferred.

[0475] Preferred groups R¹ and R² are as specified with reference toformula (A).

[0476] An illustrative example is compound 173.

[0477] According to a tenth aspect, the present invention is relative toanother sub-class of compounds (A) comprising compounds having thefollowing formula (X), which are analogous to compounds disclosed byWolin et al. (Bioorg. & Med. Chem. Lett., 8, 2157 (1998)):

[0478] wherein:

[0479] R¹ and R² are as defined with reference to formula (A);

[0480] R¹ _(X) is H or CH₃;

[0481] R² _(X) is selected from a phenyl optionally substituted with ahalogen atom, preferably chlorine, a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, CF₃,OCF₃, NO₂, NH₂; or a CH₂-phenyl optionally substituted asabove-specified;

[0482] n_(X) is from 0 to 3.

[0483] n_(x) is preferably 1. R² is preferably a phenyl group,especially a mono-substituted phenyl group.

[0484] Preferred R¹ and R² are as above-specified for formula (A).

[0485] Compound 174 is illustrative of compounds (X).

[0486] According to a eleventh aspect, the invention is directed tonon-imidazole compounds which are analogous to those disclosed in WO96/38142.

[0487] Thus, another sub-class of compounds (A) of the invention isdirected to compounds having the following formula (XI):

[0488] where R¹ and R² are as defined with reference to formula (A);

[0489] where A^(XI) is —NHCO—, N(CH₃)—CO—, —NHCH₂—, —N(CH₃)—CH₂—,—CH═CH—, —COCH₂—, CH₂CH₂—, —CH(OH)CH₂—, or —C≡C—;

[0490] X^(XI) is H, CH₃, NH₂, NH(CH₃), N(CH₃)₂, OH, OCH₃, or SH;

[0491] R₂ ^(XI) is hydrogen or a methyl or ethyl group;

[0492] R₃ ^(XI) is hydrogen or a methyl or ethyl group;

[0493] n_(XI) is 0, 1, 2, 3, 4, 5 or 6; and

[0494] R₁ ^(XI) is selected from the group consisting of C₃ to C₈cycloalkyl; phenyl or substituted phenyl; decahydronaphthalene andoctahydroindene; or

[0495] R₁ ^(XI) and X^(XI) may be taken together to denote a 5,6 or 6,6saturated bicyclic ring structure when X^(XI) is NH, O, S, or SO₂.

[0496] Preferably for compounds of formula (XI):

[0497] A^(XI) is —NHCO—, —N(CH₃)—CO—, —NHCH₂—, —N(CH₃)—CH₂—, —CH═CH—,—COCH₂—, —CH₂CH₂—, —CH(OH)CH₂—, or —C≡C—;

[0498] X^(XI) is H, CH₃, NH₂, NH(CH₃), N(CH₃)₂, OH, OCH₃, or SH;

[0499] R₂ ^(XI) is hydrogen or a methyl or ethyl group;

[0500] R₃ _(XI) is hydrogen or a methyl or ethyl gorup;

[0501] n^(XI) is 0, 1, 2, 3, 4, 5, or 6; and

[0502] R₁ ^(XI) is selected from the group consisting of (a) C₃ to C₈cycloalkyl; (b) phenyl or substituted phenyl; (d) heterocyclic (e)decahydronaphthalene and (f) octahydroindene; or

[0503] R₁ ^(XI) and X^(XI) may be taken together to denote a 5,6 or 6,6saturated bicyclic ring structure when X^(XI) can be NH, O, or S.

[0504] More preferably, the present invention provides compounds

[0505] where A^(XI) is —NHCH₂—, —N(CH₃)—CH₂—, —CH═CH—,

[0506] COCH₂—, —CH₂CH₂, —CH(OH)CH₂—, or —C≡C—;

[0507] X^(XI) is H, CH₃, NH₂, NH(CH₃), N(CH₃)₂, OH, OCH₃, or SH;

[0508] R^(XI) ₂ is hydrogen or a methyl or ethyl group;

[0509] R^(XI) ₃ is hydrogen or a methyl or ethyl group;

[0510] n^(XI) is 0, 1, 2, 3, 4, 5, or 6; and

[0511] R^(XI) ₁ is selected from the group consisting of (a) C₃ to C₈cycloalkyl; (b) phenyl or substituted phenyl; (d) heterocyclic; (e)decahydronaphthalene and (f) octahydroindene; or

[0512] R^(XI) ₁ and X^(XI) may be taken together to denote a 5,6 or 6,6saturated bicyclic ring structure when X^(XI) can be NH, O, or S.

[0513] Most preferably, the present invention provides compounds whereA^(XI) is —CH═CH or —C≡C—;

[0514] X^(XI) is H, CH₃ or NH₂;

[0515] R₂ ^(XI) and R₃ _(XI) are H;

[0516] n^(XI) is 1, 2, or 3;

[0517] R₁ ^(XI) is selected from the group consisting of (a) C₃ to C₈cycloalkyl; (b) phenyl or substituted phenyl; (d) heterocyclic; (e)decahydronaphthalene and (e octahydroindene; or

[0518] R₁ ^(XI) and X^(XI) may be taken together to denote a 5,6 or 6,6saturated bicyclic ring structure when X^(XI) is NH, O, or S.

[0519] The term “substituted phenyl” as used herein refers to a phenylgroup substituted by one or more groups such as alkyl, halogen, amino,methoxy and cyano groups.

[0520] The term “alkyl” refers to straight or branched chain radicals.Representative examples of alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and the like.

[0521] Compounds (XI) where A^(XI) is —CH═CH— or —C≡C—, X^(XI), R₂ ^(XI)and R₃ ^(XI) are each H, n_(XI) is 1 and R₁ ^(XI) is a C₃-C8 cycloalkyl,are especially preferred.

[0522] R¹ and R² are preferably selected as above-indicated in referenceto formula (A).

[0523] Representative particularly preferred compounds are compounds177, 178 or 179.

[0524] According to a twelfth aspect, the invention concernsnon-imidazole compounds which are analogous to those disclosed in WO96/38141.

[0525] Thus, the invention is relative to compounds having the followingformula (XII):

[0526] where R¹ and R² are as defined in reference to formula (A),

[0527] where R₂ ^(XII) is a hydrogen or a methyl or ethyl group;

[0528] R₃X^(II) is a hydrogen or a methyl or ethyl group;

[0529] n^(XII) is 0, 1, 2, 3, 4, 5, or 6; and

[0530] R₁ ^(XII) is selected from the group consisting of (a) C₃ to C₈cycloalkyl; (b) phenyl substituted or not by one or more groups such asa halogen atom, a lower alkyl or cycloalkyl, a trifluoromethyl, aryl,alkoxy, α-alkyloxyalkyl, aryloxy, nitro, formyl, alkanoyl, aroyl,arylalkanoyl, amino, carboxamido, cyano, alkyloximino, alkylalkoximino,aryloximino, α-hydroxyalkyl, alkenyl, alkynyl, sulphamido, sulfamoyl,sulphonamido, carboxamide, carbonylcycloalkyl, alkylcarbonylalkyl,carboalkoxy, arylalkyl or oxime group, or two substituants takentogether with the carbon atoms of the phenyl ring to which it is fusedform 5- or 6-membered saturated or unsaturated ring or a benzene ring ;(c) alkyl; (d) heterocyclic; (e) decahydronaphthalene; and (f)octahydroindene;

[0531] with the provisos that

[0532] when X^(XII) is H, A^(XII) can be —CH₂CH₂—, —COCH₂—, —CONH—,—CON(CH₃)—, —CH═CH—, —C≡C—, —CH₂—NH—, —CH₂—N(CH₃)—, —CH(OH)CH₂—,—NH—CH₂—, —N(CH₃)—CH₂—, —CH₂O—, —CH₂S—, or —NHCOO—;

[0533] when X^(XII) is NH₂, NH(CH₃), N(CH₃)₂, OH, OCH₃, CH₃, SH or SCH₃;A^(XII) can be —NHCO—, —N(CH₃)—CO—, —NHCH₂—, —N(CH₃)—CH₂—, —CH═CH—,—COCH₂—, —CH₂CH₂—, —CH(OH)CH₂—, or —C≡C—; and

[0534] when R₁ ^(XII) and X^(XII) taken together denote a 5,6 or 6,6saturated bicyclic ring structure X^(XII) can be NH, O, or S.

[0535] The term “alkyl” as used herein refers to straight or branchedchain radicals derived from saturated hydrocarbons by the removal of onehydrogen atom. Representative examples of alkyl groups include methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,and the like.

[0536] The term “substituted phenyl” as used herein refers to a phenylgroup substituted by one or more groups such as alkyl, halogen, amino,methoxy, and cyano groups.

[0537] The term “bicyclic alkyl” as used herein refers to an organiccompound having two ring structures connected to an alkyl group. Theymay or may not be the same type of ring and the rings may be substitutedby one or more groups. Representative bicyclic alkyl groups includeadamanthyl, decahydronaphthalene and norbomane.

[0538] The cyclopropane attached to the NR¹R² moiety is preferably intrans configuration.

[0539] More preferably, the present invention provides compounds of thegeneral formula (XII):

[0540] where A^(XII) is —CONH, —CH═CH—, —NHCOO—, or —C≡C—;

[0541] X^(XII) is H or NH₂;

[0542] R₂ ^(XII) and R₃X^(II) are H;

[0543] n_(XII) is 0, 1, 2 or 3;

[0544] R₁ ^(XII) is cyclohexyl, phenyl or substituted phenyl.

[0545] In compounds (XII), A^(XII) is especially —CH═CH— or —C≡C—;

[0546] R₂ ^(XII), R₃ ^(XII) and X^(XII) are each especially a hydrogenatom;

[0547] n_(XII) is preferably 1 and R₁ ^(XII) is especially an alkylgroup.

[0548] R¹ and R² are preferably selected as above-indicated withreference to formula (A).

[0549] Representative example of compounds (XII) is compound 180.

[0550] According to a thirteenth aspect, the invention is directed tonon-imidazole compounds analogous to those disclosed in WO 95/11894.

[0551] Thus, the present invention is relative to a sub-class ofcompounds (A) comprising compounds having the following formula (XIII):

[0552] wherein R¹ and R² are as defined with reference to formula (A)

[0553] wherein D^(XIII) is CH₂ or CH₂—CH₂, Z^(XIII) represents sulfur(S) or oxygen (O), preferably O, X_(XIII) is 0 or 1, n_(XIII) is aninteger from 0 to 6,

[0554] and R₂ ^(XIII) represents a substituted or unsubstituted linearchain or branched chain alkyl group of up to about 20 carbon atoms, asubstituted or unsubstituted carbocyclic group of up to about 20 carbonatoms including mono and bicyclic moieties, and a substituted or anunsubstituted aryl group of up to about 20 carbon atoms, or anycombination of above-mentioned groups, or salts thereof and with thesubstituants being represented by one or more groups such as a halogenatom, a lower alkyl or cycloalkyl, a trifluoromethyl, aryl, alkoxy,α-alkyloxyalkyl, aryloxy, nitro, formyl, alkanoyl, aroyl, arylalkanoyl,amino, carboxamido, cyano, alkyloximino, alkylalkoximino, aryloximino,α-hydroxyalkyl, alkenyl, alkynyl, sulphamido, sulfamoyl, sulphonamido,carboxamide, carbonylcycloalkyl, alkylcarbonylalkyl, carboalkoxy,arylalkyl or oxime group, or two substituants taken together with thecarbon atoms of the phenyl ring to which it is fused form 5- or6-membered saturated or unsaturated ring or a benzene ring.

[0555] In a specific embodiment, R₂ ^(XIII) can represents adisubstituted methyl, such as but not limited to dicyclohexyl methyl(—CH(C₆H₁₁)₂), diphenyl methyl (—CH(C₆H₅)₂), and the like. If R₂ ^(XIII)is tert-butyl, cyclohexyl, or dicyclohexylmethyl, X_(XIII) or n_(XIII)must not be 0. If R₂ ^(XIII) is adamantane, the sum of x_(XIII) andn_(XIII) must be greater than 1.

[0556] In a preferred embodiment, D^(XIII) is CH₂—CH₂, resulting in apiperidine ring structure. However, it is contemplated that D^(XIII) canbe CH₂, yielding a pyrrolidine ring structure. In yet anotherembodiment, D^(XIII) can be (CH₂)₃, yielding a cycloheptimide (sevenmembered heterocycle with one nitrogen).

[0557] In a specific embodiment, a tetramethylene bound to the amide orcarbamate group is used. Preferably a cyclic alkyl or aryl group islinked to the amide or carbamate via the straight chain alkyl group. Ina specific embodiment, tetramethylene cyclohexane (cyclohexylbutyl) isbound to an amide. Although specific hydrophobic alkyl and aryl groupshave been mentioned, one of ordinary skill in the art will recognizethat there are many possible hydrophobic groups for use in the compoundsof the invention. These fall within the scope of the instant invention.

[0558] Thus, R₂ ^(XIII) can be one or more bulky substituent groups. Asstated above, in a preferred aspect of the invention, the bulkysubstituents are removed from the amide or carbamate group on thepiperidyl, by increasing n_(XIII). In one embodiment, R₂ ^(XIII) is CHR₃^(XIII)R₄ ^(XIII), in which n_(XIII) is 3 or 4 and R₃ ^(XIII) and R₄^(XIII) are cyclohexyl, phenyl, or the like. R₃ ^(XIII) and R₄ ^(XIII)can be the same group or different groups. In another embodiment, R₂^(XIII) is decalin or adamantane or the like. If R₂ ^(XIII) isadamantane, preferably n_(XIII) is greater than 1, but the sum ofx_(XIII) and n_(XIII) must be greater than 1.

[0559] As used herein, the phrase linear chain or branched chained alkylgroups of up to about 20 carbon atoms means any substituted orunsubstituted acyclic carbon-containing compounds, including alkanes,alkenes and alkynes. Examples of alkyl groups include lower alkyl, forexample, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl ortert-butyl; upper alkyl, for example, octyl, nonyl, decyl, and the like;and lower alkylene, for example, ethylene, propylene, propyldiene,butylene, butyldiene, and the like. The ordinary skilled artisan isfamiliar with numerous linear and branched alkyl groups, which are withthe scope of the present invention.

[0560] In addition, such alkyl group may also contain varioussubstituents in which one or more hydrogen atoms has been replaced by afunctional group. Functional groups include but are not limited tohydroxyl, amino, carboxyl, amide, ester, ether, and halogen (fluorine,chlorine, bromine and iodine), to mention but a few.

[0561] As used herein, substituted and unsubstituted carbocyclic groupsof up to about 20 carbon atoms means cyclic carbon-containing compounds,including but not limited to cyclopentyl, cyclohexyl, cycloheptyl,admantyl, and the like. Such cyclic groups may also contain varioussubstituents in which one or more hydrogen atoms has been replaced by afunctional group. Such functional groups include those described above,and lower alkyl groups as describe above. The cyclic groups of theinvention may further comprise a heteroatom. For example, in a specificembodiment, R₂ ^(XIII) is cyclohexanol.

[0562] As used herein, substituted and unsubstituted aryl groups means ahydrocarbon ring bearing a system of conjugated double bonds, usuallycomprising six or more even number of π(pi) electons. Examples of arylgroups include, by are not limited to, phenyl, naphthyl, anisyl, toluyl,xylenyl and the like. According to the present invention, aryl alsoincludes heteroaryl groupss, e.g., pyrimidine or thiophene. These arylgroups may also be substituted with any number of a variety offunctional groups. In addition to the functional groups described abovein connection with substituted alkyl groups and carbocyclic groups,functional groups on the aryl groups can be nitro groups.

[0563] As mentioned above, R₂ ^(XIII) can also represents anycombination of alkyl, carbocyclic or aryl groups, for example,1-cyclohexylpropyl, benzyl cyclohexylmethyl, 2-cyclohexylpropyl,2,2-methylcyclohexylpropyl, 2,2-methylphenylpropyl,2,2-methylphenylbutyl.

[0564] In a specific embodiment, R₂ represents cyclohexane, andn_(XIII)=4 (cyclohexylvaleroyl). In another specific embodiment, R₂^(XIII) represents cinnamoyl.

[0565] Particularly preferred are compounds (XIII) wherein Z^(XIII) isan oxygen atom and wherein x_(XIII) is 0 or 1, n_(XIII) is an integerfrom 0 to 6, more preferably n_(XIII)=3-6, and most preferablyn_(XIII)=4, and R₂ ^(XIII) is as defined above. Examples of preferredalkyl groups for R₂ ^(XIII) include but are not limited to cyclopentyl,cyclohexyl, admantane methylene, dicyclohexyl methyl, decanyl andt-butyryl and the like. Examples of preferred aryl and substituted arylgroups include but are not limited to phenyl, aryl cyclohexyl methyl andthe like.

[0566] Preferred R¹ and R² are selected as indicated with reference toformula (A).

[0567] Representative examples are compounds 123 and 176.

[0568] According to a fourteenth aspect, the present invention isdirected to compounds analogous to those disclosed in WO 93/12107.

[0569] Thus, a sub-class of compounds (A) of the invention concernscompounds having the following formula (XIV)

[0570] wherein R¹ and R² are as defined in reference of formula (A);

[0571] (A) m_(XIV) is an integer selected from the group consisting of:1 and 2;

[0572] (B) n_(XIV) and p_(XIV) are intergers and are each independentlyselected from the group consisting of: 0, 1, 2, 3, and 4 such that thesum of n_(XIV) and p_(XIV) is 4 and T^(XIV) is a 6-membered ring;

[0573] (C) R³ _(XIV) and R⁴ _(XIV) are each independently bound to thesame or different carbon atom of ring T^(XIV) such that there is onlyone R³ _(XIV) group and one R⁴ _(XIV) group in ring T^(XIV), and each R¹_(XIV), R² _(XIV), R³ _(XIV) and R⁴ _(XIV) is independently selectedfrom the group consisting of:

[0574] (1) H;

[0575] (2) C₁ to C₆ akyl; and

[0576] (3) —(CH₂)_(qXIV)—R⁶ _(XIV) wherein q_(XIV) is an integer of: 1to 7, and R⁶ _(XIV) is selected from the group consisting of: phenyl,substituted phenyl, —OR⁷ _(XIV), —C(O)OR⁷ _(XIV), —C(O)R⁷ _(XIV),—OC(O)R⁷ _(XIV), —C(O)NR⁷ _(XIV)R_(XIV), CN and —SR⁷ _(XIV) wherein R⁷_(XIV) and R⁸ _(XIV) are as defined below, and wherein the substituentson said substituted phenyl are each independently selected from thegroup consisting of: —OH, —O—(C₁ to C₆)alkyl, halogen, C₁ to C₆ alkyl,—CF₃, —CN, and —NO₂, and wherein said substituted phenyl contains from 1to 3 substituents;

[0577] (D) R⁵ _(XIV) is selected from the group consisting of:

[0578] (1) H;

[0579] (2) C₁ to C₂₀ alkyl;

[0580] (3) C₃ to C₆ cycloalkyl;

[0581] (4) —C(O)OR^(7′) _(XIV); wherein R^(7′) _(XIV) is the same as R⁷_(XIV) defined below except that R^(7′) _(XIV) is not H;

[0582] (5) —C(O)R^(7′) _(XIV);

[0583] (6) —C(O)NR^(7′) _(XIV)R⁸ _(XIV)v;

[0584] (7) allyl;

[0585] (8) propargyl; and

[0586] (9) —(CH₂)_(q)—R⁶ _(XIV) wherein q_(XIV) and R⁶ _(XIV) are asdefined above, and when q_(XIV) is equal to 1, then R⁶ _(XIV) is not OHor SH;

[0587] (E) R⁷ _(XIV) and R⁸ _(XIV) are each independently selected fromthe group consisting of: H, C₁ to C₆ alkyl, and C₃ to C₆ cycloalkyl;

[0588] (F) the dotted line (

) represents a double bond that is optionally present when m_(XIV) is 1,and n_(XIV) is not 0, and p is not 0 (i.e., the nitrogen in the ring isnot bound directly to the carbon atom bearing the double bond), and whensaid double bond is present then R² _(XIV) is absent; and

[0589] (G) when m_(XIV) is 2, each R¹ _(XIV) is the same or differentsubstituent for each m_(XIV), and each R² _(XIV) is the same ordifferent substituent for each m_(XIV), and at least two of thesubstituents R¹ _(XIV) and/or R² _(XIV) are H.

[0590] Those skilled in the art will appreciate that the total number ofsubstituents on each of the —(C)_(n) ^(XIV)— and —(C)_(p) ^(XIV)— groupsis two, and that such substituents are independently selected from thegroup consisting of hydrogen, R³ _(XIV) and R⁴ _(XIV) such that there isa total of only one R³ _(XIV) and one R⁴ _(XIV) substituent in ringT^(XIV).

[0591] As used herein the following terms have the following meaningsunless indicated otherwise:

[0592] alkyl—represents a straight or branched, saturated hydrocarbonchain having from 1 to 20 carbon atoms;

[0593] cycloalkyl—represents a saturated carbocyclic ring having from 3to 6 carbon atoms;

[0594] halogen (halo)—represents fluoro, chloro, bromo or iodo.

[0595] Preferably, for compounds of formula (XIV) m is 1; R⁵ _(XIV) isselected from the group consisting of H and C₁ to C₁₅ alkyl; and R¹_(XIV) to R⁴ _(XIV) are each independently selected from the groupconsisting of: H, C₁ to C₆ alkyl, and —(CH₂)_(qXIV)—R⁶ _(XIV) wherein R⁶_(XIV) is phenyl. Most preferably, R⁵ _(XIV) is selected from the groupconsisting of H and C₁ to C₆ alkyl with H and methyl being even morepreferable; and R³ _(XIV) and R⁴ _(XIV) are each independently selectedfrom the group consisting of: H and methyl.

[0596] Representative compounds of this invention include compounds ofthe formula:

[0597] For formula (XIVa), (XIVb) or (XIVc), R⁵ _(XIV) is preferably Hor CH₃; R³ _(XIV) and R⁴ _(XIV) are preferably each an hydrogen atom.

[0598] Preferred R¹ and R² are as specified for formula (A).

[0599] According to a fifteenth aspect, the invention is directed tocompounds analogous to those disclosed in WO 93/12108.

[0600] Thus, the invention concerns compounds having the followingformula (XV):

[0601] wherein R¹ and R² are as defined in reference to formula (A)

[0602] (A) m_(XV) is an integer selected from the group consisting of:0, 1, and 2;

[0603] (B) n_(XV) and p_(XV) are integers and are each independentlyselected from the group consisting of: 0, 1, 2, and 3 such that the sumof n_(XV) and p_(XV) is 2 or 3 such that when the sum of n_(XV) andp_(XV) is 2, T^(XV) is a 4-membered ring and when the sum of n_(XV) andp_(XV) is 3, T^(XV) is a 5-membered ring;

[0604] (C) each R¹ _(XV), R² _(XV), R³ _(XV), R⁴ _(XV), R⁶ _(XV), R⁷_(XV) and R⁸ _(XV) is independently selected from the group consistingof:

[0605] (1) H;

[0606] (2) C₁ to C₆ alkyl;

[0607] (3) C₃ to C₆ cycloalkyl; and

[0608] (4) —(CH₂)_(q) ^(XV)—R⁹ _(XV) wherein q_(XV) is an integer of: 1to 7, and R⁹ _(XV) is selected from the group consisting of: phenyl,substituted phenyl, —OR¹⁰ _(XV), —C(O)OR¹⁰ _(XV), —C(O)R¹⁰ _(XV),—OC(O)R¹⁰ _(XV), —C(O)NR¹⁰ _(XV)R¹¹ _(XV), CN and —SR¹⁰ _(XV) whereinR¹⁰ _(XV) and R¹¹ _(XV) are as defined below, and wherein thesubstituents on said substituted phenyl are each independently selectedfrom the group consisting of: —OH, —O—(C₁ to C₆) alkyl, halogen, C₁ toC₆ alkyl, —CF₃, —CN, and —NO₂, and wherein said substituted phenylcontains from 1 to 3 substituents; examples of —(CH₂)_(qXV)—R⁹ _(XV)include benzyl, substituted benzyl and the like, wherein thesubstitutents on the substituted benzyl are as defined above for saidsubstituted phenyl;

[0609] (D) R⁵ _(XV) is selected from the group consisting of:

[0610] (1) H;

[0611] (2) C₁ to C₂₀ alkyl;

[0612] (3) C₃ to C₆ cycloalkyl;

[0613] (4) —C(O)OR^(10′) _(XV); wherein R^(10′) _(XV) is the same as R¹⁰_(XV) defined below except that R^(10′) _(XV) is not H;

[0614] (5) —C(O)R¹⁰ _(XV);

[0615] (6) —C(O)NR¹⁰ _(XV)R¹¹ _(XV);

[0616] (7) allyl;

[0617] (8) propargyl; and

[0618] (9) —(CH₂)_(q) ^(XV)—R⁹ _(XV), wherein q_(XV) and R⁹ _(XV) are asdefined above with the proviso that when q_(XV) is 1 then R⁹ _(XV) isnot —OH or —SH;

[0619] (E) R¹⁰ _(XV) and R¹¹ _(XV) are each independently selected fromthe group consisting of: H, C₁ to C₆ alkyl, and C₃ to C₆ cycloalkyl;and, for the substituent —C(O)NR¹⁰ _(XV)R_(XV) ¹¹, R¹⁰ _(XV) and R¹¹_(XV), together with the nitrogen to which they are bound, can form aring having 5, 6, or 7 atoms;

[0620] (F) the dotted line (

) represents a double bond that is optionally present when m_(XV) is 1,and T^(XV) is a 5-membered ring, and n_(XV) is not 0, and p_(XV) is not0 (i.e., the nitrogen in the ring is not bound directly to the carbonatom bearing the double bond), and when said double bond is present thenR² _(XV) and R⁸ _(XV) are absent;

[0621] (G) when m_(XV) is 2, each R¹ _(XV) is the same or differentsubstituent for each m_(XV), and each R² _(XV) is the same or differentsubstituent for each m_(XV);

[0622] (H) when n_(XV) is 2 or 3, each R³ _(XV) is the same or differentsubstituent for each n_(XV), and each R⁴ _(XV) is the same or differentsubstituent for each n_(XV); and

[0623] (I) when p_(XV) is 2 or 3, each R⁶ _(XV) is the same or differentsubstituent for each p, and each R⁷ _(XV) is the same or differentsubstituent for each p_(XV).

[0624] As used herein the following terms have the following meaningsunless indicated otherwise:

[0625] alkyl—represents a straight or branched, saturated hydrocarbonchain having from 1 to 20 carbon atoms;

[0626] cycloalkyl—represents a saturated carbocyclic ring having from 3to 6 carbon atoms; and

[0627] halogen (halo)—represents fluoro, chloro, bromo or iodo.

[0628] Preferably, for compounds of formula (XV) m_(XV) is 0 or 1; R⁵_(XV) is selected from the group consisting of H and C₁ to C₂₀ alkyl;and R¹ _(XV) to R⁴ _(XV) and R⁶ _(XV) to R⁸ _(XV) are each independentlyselected from the group consisting of: H, C₁ to C₆ alkyl, and—(CH₂)_(qXV)R⁹ _(XV) wherein R⁹ _(XV) is phenyl. Most preferably, R⁵_(XV) is selected from the group consisting of H and methyl; and R¹_(XV), R² _(XV), R³ _(XV), R⁴ _(XV), R⁷ _(XV), and R⁸ _(XV) are eachindependently selected from the group consisting of: H, methyl, ethyl,pentyl, benzyl, and 2-phenylethyl.

[0629] Representative compounds of this invention include compounds ofthe formula:

[0630] wherein m_(XV) and R¹ _(XV) to R⁸ _(XV) are as defined forformula (XV)

[0631] Compounds (XVc) or (XVd) are preferred.

[0632] Representative compounds (XVa) to (XVd) are those wherein R⁵_(XV) is H or CH₃.

[0633] Preferably, only one or two of substituents R³ _(XV), R⁴ _(XV),R⁶ _(XV), R⁷ _(XV), R³ _(XV) is different from H and representsespecially CH₃.

[0634] R¹ and R² are preferably selected as indicated in reference toformula (A).

[0635] According to a sixteenth aspect, the invention is directed tocompounds analogous to those disclosed in WO 92/15567.

[0636] Thus, the invention is relative to a sub-class of compounds (A)consisting of compounds having the following formula (XVI)

[0637] wherein R¹ and R² are as defined in reference to formula (A)

[0638] Z^(XVI) is a group of the formula (CH₂)_(mXVI) whereinm_(XVI)=1-5 or a group of the formula:

[0639] wherein R⁶ _(XVI)=(C₁-C₃)alkyl

[0640] R⁷ _(XVI)=(C₁-C₃)alkyl;

[0641] wherein Z^(XVI) may optionally comprise other substituentsselected such that the activity of the derivative is not negativelyaffected,

[0642] X^(XVI) represents S, NH, or CH₂

[0643] R¹ _(XVI) represents hydrogen, (C₁-C₃)alkyl-, aryl(C₁-C₁₀)alkyl,wherein aryl may optionally be substituted, aryl,(C₅-C₇)cycloalkyl(C₁-C₁₀)alkyl-, or a group of the formula:

[0644] wherein n_(XVI)=1-4, R⁸ _(XVI) is aryl, aryl(C₁-C₁₀)alkyl-,(C₅-C₇)cycloalkyl- or (C₅-C₇) cycloalkyl(C₁-C₁₀)alkyl-, and R⁹ _(XVI) ishydrogen, (C₁-C₁₀)alkyl- or aryl; R₂ _(XVI) and R₅ ^(XVI) representhydrogen, (C₁-C₃)alkyl-, aryl or arylalkyl-, wherein aryl may optionallybe substituted; wherein aryl is phenyl, substituted phenyl, naphthyl,substituted napththyl, pyridyl or substituted pyridyl;

[0645] R₂ _(XVI) and R₅ _(XVI) are preferably a hydrogen atom.

[0646] m_(XVI) is preferably 2 or 3

[0647] X_(XVI) is preferably S or NH

[0648] R₁ ^(XVI) is preferably selected from H or an optionallysubstituted aryl.

[0649] Preferred R¹ and R² are selected as specified for formula A.

[0650] According to a seventeenth aspect, a sub-class of compounds (A)of the invention comprises compounds having the following formula(XVII), which can be considered as analogous to those disclosed in EP680 960:

[0651] Wherein m_(XVII) represents an integer of from 4 to 6.

[0652] R⁴ _(XVII) represents a hydrogen atom, a linear or branched alkylgroup, a cycloalkyl group, a cycloalkylalkyl group, a substituted orunsubstituted aryl group or a substituted or unsubstituted aralkylgroup; and Z^(XVII) represents R⁵ _(XVII) or A^(XVII)-R⁸ _(XVII),wherein A^(XVII) represents S or O, R₅ _(XVI) represents a hydrogenatom, a lower alkyl group, a substituted or unsubstituted aryl group ora substituted or unsubstituted aralkyl group, and R₆ ^(XVII) representsa lower alkyl group, a lower alkenyl group, a lower alkynyl group or asubstituted or unsubstituted aralkyl group;

[0653] The lower alkyl groups are preferably linear or branched alkylgroups having 1 to 6 carbon atoms. Specific examples thereof includemethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl and n-hexyl groups.

[0654] The linear or branched alkyl groups are preferably those having 1to 8 carbon atoms. Specific examples thereof include methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl and1,2,2-trimethylpropyl groups.

[0655] The cycloalkyl groups are preferably those having 3 to 10 carbonatoms. The cycloalkyl groups include not only monocycloalkyl groups (forexample, cyclopentyl, cyclohexyl and cycloheptyl) but alsopolycycloalkyl groups (for example, bicycloalkyl and tricycloalkyl).Examples of the bicycloalkyl groups include norbomyl (for example,exo-2-norbomyl and endo-2-norbomyl), 3-pinanyl andbicyclo[2.2.2]oct-2-yl groups, while examples of the tricycloalkylgroups include adamantyl groups (for example, 1-adamantyl and2-adamantyl). Such a cycloalkyl group may be substituted by alkylgroup(s), etc.

[0656] The cycloalkylalkyl groups are preferably those composed of acycloalkyl group having 3 to 10 carbon atoms with a linear or branchedalkyl group having 1 to 3 carbon atoms. Specific examples thereofinclude 1-cyclohexylethyl and 1-cyclopropylethyl groups.

[0657] The lower alkenyl groups are preferably linear or branchedalkenyl groups having 3 to 6 carbon atoms. Specific examples thereofinclude allyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, cis-2-butenyl,trans-2-butenyl and 3-methyl-2-butenyl groups.

[0658] The lower alkynyl groups are preferably those having 3 to 6carbon atoms. A specific example thereof includes a 2-propynyl group.

[0659] The substituted aryl groups are preferably phenyl and naphthylgroups which may be substituted by halogen atoms and trifluoromethyl,lower alkyl, lower alkoxy, lower alkylthio, cyano and nitro groups.

[0660] Specific examples thereof include phenyl, 1-naphthyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl,3-fluorophenyl, 4-fluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl,2-tolyl and 3-tolyl groups.

[0661] The aralkyl groups are preferably benzyl, diarylmethyl and tritylgroups.

[0662] The substituted aralkyl groups are preferably arylalkyl groupscomposed of a phenyl or naphthyl group, which may be substituted byhalogen atoms and trifluoromethyl, lower alkyl, lower alkoxy, loweralkylthio, cyano and nitro groups, and a linear or branched alkyl grouphaving 1 to 4 carbon atoms.

[0663] Specific examples thereof include benzyl, α-methylbenzyl,phenethyl, 3-phenylpropyl, 4-phenylbutyl, 4-chlorobenzyl,4-fluorobenzyl, 4-methoxybenzyl, 4-chloro-α-methylbenzyl,4-fluoro-αmethylbenzyl and 4-methoxy-a-methylbenzyl groups.

[0664] Among the compounds represented by the general formula (XVII)preferable examples include those wherein:

[0665] m_(XVII) is from 4 to 6;

[0666] R⁴ _(XVII) is a hydrogen atom; a linear or branched alkyl grouphaving 1 to 8 carbon atoms, a cycloalkyl group having 3 to 10 carbonatoms, a cycloalkylalkyl group composed of a cycloalkyl moiety having 3to 10 carbon atoms and an alkyl moiety having 1 to 3 carbon atoms, asubstituted or unsubstituted aryl group or a substituted orunsubstituted aralkyl group carrying an alkyl moiety having 1 to 4carbon atoms;

[0667] R⁵ ^(XVII) is a hydrogen atom, an alkyl group having 1 to 6carbon atoms, a substituted or unsubstituted aryl group or a substitutedor unsubstituted aralkyl group carrying an alkyl moiety having 1 to 4carbon atoms; and

[0668] R⁶ _(XVII) is an alkyl group having 1 to 6 carbon atoms, analkenyl group having 3 to 6 carbon atoms, an alkynyl group having 3 to 6carbon atoms or a substituted or unsubstituted aryl group.

[0669] Preferable examples of the compounds represented by the generalformula (XVII) are those satisfying the following requirements:

[0670] (1) A compound wherein m^(XVII) is 5 and R¹, R² and R³ are each ahydrogen atom.

[0671] (2) A compound wherein R⁴ _(XVII) is a cycloalkyl group, such asmonocycloalkyl, bicycloalkyl and tricycloalkyl groups. A preferableexample of the monocycloalkyl group is a cyclohexyl group. A preferableexample of the bicycloalkyl group is a norbornyl group, more preferablya 2-exo-norbornyl group. A preferable example of the tricycloalkyl groupis an adamantyl group, more preferably a 1-adamantyl group.

[0672] (3) A compound wherein R⁴ _(XVII) is a substituted orunsubstituted phenyl group or a substituted or unsubstituted phenylalkylgroup.

[0673] (4) A compound wherein R⁵ _(XVII) is a hydrogen atom.

[0674] (5) A compound wherein A^(XVII) is S and R⁶ _(XVII) is a loweralkyl group.

[0675] (6) A compound wherein a lower alkyl group is a methyl group.

[0676] R¹ and R² are preferably selected as specified for the formula(A).

[0677] According to a eighteenth aspect, the invention is directed tonon imidazole compounds having the following formula (XVIII), analogousto those disclosed in Van der Goot et al. (Eur. J. Med. Chem. (1992) 27,511-517):

[0678] in which:

[0679] R¹ and R² are as defined with reference to formula (A);

[0680] R^(e) _(XVIII) is H, alkyl or cycloalkyl;

[0681] R^(f) _(XVIII) is H or halogen, in particular Cl, F, Br, or analkyl;

[0682] t_(XVIII) is 1 to 3;

[0683] u_(XVIII) is 1 to 4.

[0684] Preferred groups R¹ and R² are as defined with reference toformula (A).

[0685] Representative example is compound 122 and 167.

[0686] According to the invention, the W residue as defined in formula(A) and in particular as illustrated by formulae (I) to (XVIII),preferably contains no imidazole moiety attached in 4(5)-position andmore preferably W contains no imidazole moiety.

[0687] The compounds according to the invention may be preparedaccording to one of the following schemes:

[0688] More specifically, compounds of formula (I) can be obtained bythe schemes 1 to 5:

[0689] In these schemes, R¹, R², R³, X and n are as defined in generalformula (I).

[0690] Me and Et are intended to mean methyl and ethyl.

[0691] Detailed synthesis procedures are given in the examples.

[0692] The compounds of formula (A) according to the invention haveantagonistic and/or agonistic properties at the histamine H₃-receptors.They affect the synthesis and release of histamine monoamines orneuropeptides in brain and peripheral tissues.

[0693] This property makes the compounds of the invention usefulderivatives in human or veterinary medicine.

[0694] Their therapeutical applications are those known forH₃-antagonist and/or agonist compounds and especially relate to thecentral nervous system disorders.

[0695] Regarding antagonistic activity, the compounds according to theinvention can be used in the treatment of Alzheimer disease, mood andattention alterations, cognitive deficits in psychiatric pathologies,obesity, vertigo and motion sickness.

[0696] Regarding agonistic activity, the compounds according to theinvention can be used in the treatment of various allergic andinflammatory diseases and as a sedative agent.

[0697] Therefore, the compounds of formula (A) according to theinvention are advantageously used as active ingredient of medicamentswhich act as ligand for H₃-receptors of histamine and in particular asan antagonist and/or agonist of H₃-receptors of histamine.

[0698] The present invention is also directed to the use of at least onefollowing compounds

[0699] 1-(5-phenoxypentyl)-piperidine

[0700] 1-(5-phenoxypentyl)-pyrrolidine

[0701] N-methyl-N-(5-phenoxypentyl)-ethylamine

[0702] 1-(5-phenoxypentyl)-morpholine

[0703] N-(5-phenoxypentyl)-hexamethyleneimine

[0704] N-ethyl-N-(5-phenoxypentyl)-propylamine

[0705] 1-(5-phenoxypentyl)-2-methyl-piperidine

[0706] 1-(5-phenoxypentyl)4-propyl-piperidine

[0707] 1-(5-phenoxypentyl)4-methyl-piperidine

[0708] 1-(5-phenoxypentyl)-3-methyl-piperidine

[0709] 1-acetyl-4-(5-phenoxypentyl)-piperazine

[0710] 1-(5-phenoxypentyl)-3,5-trans-dimethyl-piperidine

[0711] 1-(5-phenoxypentyl)-3,5-cis-dimethyl-piperidine

[0712] 1-(5-phenoxypentyl)-2,6-cis-dimethyl-piperidine

[0713] 4-carboethoxy-1-(5-phenoxypentyl)-piperidine

[0714] 3-carboethoxy-1-(5-phenoxypentyl)-piperidine

[0715] 1-[3-(4-cyclopropylcarbonylphenoxy) propyl]-piperidine

[0716] 1-[3-(4-acetylphenoxy)-2-R-methylpropyl] piperidine

[0717] 1-[3-(4-cyanophenoxy)propyl]-4-methylpiperidine

[0718] 1-[3-(4-cyanophenoxy)propyl]-3-methylpiperidine

[0719] 1-[3-(4-acetylphenoxy)-2-S-methylpropyl] piperidine

[0720] 1-{3-[4-(3-oxobutyl)phenoxy] propyl}piperidine

[0721] 1-[3-(4-cyano-3-fluorophenoxy)propyl] piperidine

[0722] 1-[3-(4-nitrophenoxy)propyl]-3-methylpiperidine

[0723] 1-[3-(4-cyanophenoxy)propyl]-2-methylpiperidine

[0724] 1-[3-(4-nitrophenoxy)propyl]-2-methylpiperidine

[0725] 1-[3-(4-nitrophenoxy)propyl]-4-methylpiperidine

[0726] 1-[3-(4-cyanophenoxy)propyl]-2,6-dimethylpiperidine

[0727] 1-[3-(4-propionylphenoxy)propyl]-3-methylpiperidine

[0728] 1-[3-(4-cyclobutylcarbonylphenoxy)propyl] piperidine

[0729] 1-[3-(4-cyclopentylcarbonylphenoxy) propyl]piperidine

[0730] 1-[3-(4-cyanophenoxy)propyl]-cis-2-methyl-5-ethylpiperidine

[0731] 1-[3-(4-cyanophenoxy)propyl]-trans-2-methyl-5-ethylpiperidine

[0732] 1-[3-(4-cyanophenoxy)propyl]-cis-3,5-dimethylpiperidine

[0733] 1-[3-(4-propionylphenoxy)propyl]4-methylpiperidine

[0734] 1-[3-(4-propionylphenoxy)propyl]-2-methylpiperidine

[0735] 1-{3-[4-(1-hydroxypropyl)phenoxy]propyl}-3-methylpiperidine

[0736] 1-{3-[4-(1-hydroxypropyl)phenoxy]propyl}-4-methylpiperidine

[0737] 1-[3-(4-propionylphenoxy)propyl]-2-methylpiperidine

[0738] 1-[3-(4-propionylphenoxy)propyl]-4-methylpiperidine methoxime

[0739] 1-[3-(4-cyanophenoxy)propyl]-trans-3,5-dimethylpiperidine

[0740] 1-[3-(4-cyclopropylcarbonylphenoxy) propyl]-trans-3,5-dimethylpiperidine

[0741] 1-[3-(4-cyclopropylcarbonylphenoxy) propyl]-cis-3,5-dimethylpiperidine

[0742] 1-[3-(4-carbomethoxyphenoxy)propyl] piperidine

[0743] 1-[3-(4-propenylphenoxy)propyl]-2-methyl piperidine

[0744] 1-[3-(4-propionylphenoxy)propyl]-2-methylpiperidine

[0745] 1-{3-[4-(1-ethoxypropyl)phenoxy]propyl}2-methyl piperidine

[0746] 1-[3-(4-propionylphenoxy)propyl]-4-methylpiperidine

[0747] 1-[3-(4-bromophenoxy)propyl]piperidine

[0748] 1-[3-(4-nitrophenoxy)propyl]piperidine

[0749] 1-[3-(4-N,N-dimethylsulfonamidophenoxy) propyl]piperidine

[0750] 1-[3-(4-isopropylphenoxy)propyl]piperidine

[0751] 1-[3-(4-sec-butylphenoxy)propyl]piperidine

[0752] 1-[3-(4-propylphenoxy)propyl]piperidine

[0753] 1-[3-(4-ethylphenoxy)propyl]piperidine

[0754] 1-(5-phenoxypentyl)-1,2,3,6-tetrahydropyridine

[0755] 1-[5-(4-nitrophenoxy)-pentyl]-pyrrolidine

[0756] 1-[5-(4-chlorophenoxy)-pentyl]-pyrrolidine

[0757] 1-[5-(4-methoxyphenoxy)-pentyl]-pyrrolidine

[0758] 1-[5-(4-methylphenoxy)-pentyl]-pyrrolidine

[0759] 1-[5-(4-cyanophenoxy)-pentyl]-pyrrolidine

[0760] 1-[5-(2-naphthyloxy)-pentyl]-pyrrolidine

[0761] 1-[5-(1-naphthyloxy)-pentyl]-pyrrolidine

[0762] 1-[5-(3-chlorophenoxy)-pentyl]-pyrrolidine

[0763] 1-[5-(4-phenylphenoxy)-pentyl]-pyrrolidine

[0764] 1-{5-[2-(5,6,7,8-tetrahydronaphthyloxy]-pentyl}-pyrrolidine

[0765] 1-[5-(3-phenylphenoxy)-pentyl]-pyrrolidine

[0766] 1-(5-phenoxypentyl)-2,5-dihydropyrrole

[0767] 1-{5-[1-(5,6,7,8-tetrahydronaphthyl)-oxy]-pentyl}-pyrrolidine

[0768] 1-(4-phenoxybutylypyrrolidine

[0769] 1-(6-phenoxyhexyl)-pyrrolidine

[0770] 1-(5-phenylthiopentyl)-pyrrolidine

[0771] 1-(4-phenylthiobutyl)-pyrrolidine

[0772] 1-(3-phenoxypropyl)-pyrrolidine

[0773] 1-[5-(3-nitrophenoxy)-pentyl]-pyrrolidine

[0774] 1-[5-(4-fluorophenoxy)-pentyl]-pyrrolidine

[0775] 1-[5-(4-nitrophenoxy)-pentyl]-3-methyl-piperidine

[0776] 1-[5-(4-acetylphenoxy)-pentyl]-pyrrolidine

[0777] 1-[5-(4-aminophenoxy)-pentyl]-pyrrolidine

[0778] 1-[5-(3-cyanophenoxy)-pentyl]-pyrrolidine

[0779] N-[3-(4-nitrophenoxy)-propyl]-diethylamine

[0780] N-[3-(4-cyanophenoxy)-propyl]-diethylamine

[0781] 1-[5-(4-benzoylphenoxy)-pentyl]-pyrrolidine

[0782] 1-{5-[4-(phenylacetyl)-phenoxy]-pentyl)pyrrolidine

[0783] N-[3-(4-acetylphenoxy)-propyl]-diethylamine

[0784] 1-[5-(4-acetamidophenoxy)-pentyl]-pyrrolidine

[0785] 1-[5-(4-phenoxyphenoxy)-pentyl]-pyrrolidine

[0786] 1-[5-(4-N-benzamidophenoxy)-pentyl]-pyrrolidine

[0787] 1-5-[4-(1-hydroxyethyl)-phenoxy]-pentyl}-pyrrolidine

[0788] 1-[5-(4-cyanophenoxy)-pentyl]-diethylamine

[0789] 1-[5-(4-cyanophenoxy)-pentyl]-piperidine

[0790] N-[5-(4-cyanophenoxy)-pentyl]-dimethylamine

[0791] N-[2-(4-cyanophenoxy)-ethyl]-diethylamine

[0792] N-[3-(4-cyanophenoxy)-propyl]-dimethylamine

[0793] N-[4-(4-cyanophenoxy)-butyl]-diethylamine

[0794] N-[5-(4-cyanophenoxy)-pentyl]-dipropylamine

[0795] 1-[3-(4-cyanophenoxy)-propyl]-pyrrolidine

[0796] 1-[3-(4-cyanophenoxy)-propyl]-piperidine

[0797] N-[3-(4-cyanophenoxy)-propyl]-hexamethyleneimine

[0798] N-[6-(4-cyanophenoxy)-hexyl]-diethylamine

[0799] N-[3-(4-cyanophenoxy)-propyl]-dipropylamine

[0800] N-3-[4-(1-hydroxyethyl)-phenoxy]-propyl-diethylamine

[0801] 4-(3-diethylaminopropoxy)-acetophenone-oxime

[0802] 1-[3-(4-acetylphenoxy)-propyl]-piperidine

[0803] 1-[3-(4-acetylphenoxy)-propyl]-3-methyl-piperidine

[0804] 1-[3-(4-acetylphenoxy)-propyl]-3,5-trans-dimethyl-piperidine

[0805] 1-[3-(4-acetylphenoxy)-propyl]-4-methyl-piperidine

[0806] 1-[3-(4-propionylphenoxy)-propyl]-piperidine

[0807] 1-[3-(4-acetylphenoxy)-propyl]-3,5-cis-dimethyl-piperidine

[0808] 1-[3-(4-formylphenoxy)-propyl]-piperidine

[0809] 1-[3-(4-isobutyrylphenoxy)-propyl]-piperidine

[0810] N-[3-(4-propionylphenoxy)-propyl]-diethylamine

[0811] 1-[3-(4-butyrylphenoxy)-propyl]-piperidine

[0812] 1-[3-(4-acetylphenoxy)-propyl]-1,2,3,6-tetrahydropyridine

[0813] α-(4-Acetylphenoxy)-α′-(4-methylpiperidino)p-xylol

[0814] α-(4-Acetylphenoxy)-α′-(3,5-cis-dimethylpiperidino)p-xylol

[0815] α-(4-Acetylphenoxy)-α′-(3,5-trans-dimethylpiperidino)p-xylol

[0816] α-(4-Acetylphenoxy)-α′-(2-methylpyrrolidino)p-xylol

[0817] α-(4-Cyclopropylcarbonylphenoxy)-α′-piperidino-p-xylol

[0818] α-(4-Cyclopropylcarbonylphenoxy)-α′-(4-methylpiperidino)p-xylol

[0819] α-(4-Cyclopropylcarbonylphenoxy)-α′-pyrrolidino-p-xylol

[0820] 3-Phenylpropyl 3-(4-methylpiperidino)propyl ether

[0821] 3-Phenylpropyl 3-(3,5-cis-dimethylpiperidino)propyl ether

[0822] 3-Phenylpropyl 3-(3,5-trans-dimethylpiperidino)propyl ether

[0823] 3-Phenylpropyl 3-(3-methylpiperidino)propyl ether

[0824] 3-Phenylpropyl 3-pyrrolidinopropyl ether

[0825] 3-(4-Chlorophenyl)propyl 3-(4-methylpiperidino)propyl ether

[0826] 3-(4-Chlorophenyl)propyl 3-(3,5-cis-dimethylpiperidino)propylether

[0827] 3-(4-Chlorophenyl)propyl3(3,5-trans-dimethylpiperidino)propylether

[0828] 4-(6-Piperidinohexylamino)quinoline

[0829] 2-Methyl 4-(3-piperidinopropylamino)quinoline

[0830] 2-Methyl 4-(6-piperidinohexylamino)quinoline

[0831] 7-Chloro-4-(3-piperidinopropylamino)quinoline

[0832] 7-Chloro-4-(4-piperidinobutylamino)quinoline

[0833] 7-Chloro-4-(8-piperidinooctylamino)quinoline

[0834] 7-Chloro-4-(10-piperidinodecylamino)quinoline

[0835] 7-Chloro-4-(12-piperidinododecylamino)quinoline

[0836] 7-Chloro-4-(4-(3-piperidinopropoxy)phenylamino)quinoline

[0837] 7-Chloro-4-(2-(4-(3-piperidinopropoxy)phenyl)ethylamino)quinoline

[0838] 4-(6-Piperidinohexanoyl)phenyl 3-piperidinopropyl ether

[0839] 5-Nitro-2-(5-piperidinopentylamino)pyridine

[0840] 3-Nitro-2-(6-piperidinopentylamino)pyridine

[0841] 5-Amino-2-(6-piperidinopentylamino)pyridine

[0842] 2-(6-Piperidinohexylamino)quinoline

[0843] N-(4-Chlorobenzyl)-N′-cyclohexyl-3-piperidinopropyl isothiourea

[0844] 2-(6-Piperidinohexylamino)benzothiazole

[0845] 10-Piperidinodecylamine

[0846] 3-Phenylpropyl 3-(N,N-diethylamino)propyl ether

[0847] N-(3-(N,N-Diethylamino)propyl)N′-phenylurea

[0848] N-Cyclohexylmethyl-N′-(3-piperidinopropyl)guanidine

[0849] N-(4-Bromobenzyl)-N′-(4-piperidinobutyl)sulphamide

[0850] 3-Chloro-N-(4-piperidinobutyl)-N-methyl-benzene sulphonamide

[0851] N-(4-Chlorobenzyl)-2-(4-piperidinomethyl) phenyl) ethan amidine

[0852] 1-(5-Cyclohexylpentanoyl)-1,4-bipiperidine

[0853] cis-1-(6-Cyclohexyl-3-hexen-1-yl)piperidine

[0854] trans-1-(6-Cyclohexyl-3-hexen-1-yl)piperidine

[0855] 1-(2-(5,5-Dimethyl-1-hexen-1-yl)cyclopropyl)piperidine

[0856] for the preparation of a medicament acting as a ligand for thehistamine H₃-receptor and in particular as an antagonist and/or agonistof the histamine H₃-receptors.

[0857] The antagonists are advantageously used as active ingredient inparticular, of medicaments having psychotropic effects, promotingwakefullness, attention, memory and improving mood, in treatment ofpathologies such as Alzheimer disease and other cognitive disorders inaged persons, depressive or simply asthenic states.

[0858] Their nootropic effects can be useful to stimulate attention andmemorization capacity in healthy humans.

[0859] In addition, these agents can be useful in treatment of obesity,vertigo and motion sickness.

[0860] It can also be useful to associate the compounds of the inventionwith other psychiatric agents such as neuroleptics to increase theirefficiency and reduce their side effects.

[0861] Application in certain form of epilepsy is also foreseen.

[0862] Their therapeutic applications involve also peripheral organsmainly a stimulant of secretions or gastro-intestinal motricity.

[0863] The compounds of the invention are particularly useful for thetreatment of CNS disorders of aged persons.

[0864] The said compounds may also be used as an agonist or partialagonist action on the said histamine receptors.

[0865] H₃ receptor agonists and partial agonists, through their cerebraleffects, mainly exert sedative, tranquillizing, antistress and analgesicactivity, indicating their use as mild sedative psychotropics, inparticular in various psychosomatic disorders.

[0866] H₃ agonists and partial agonists are also indicated in thetreatment of migraine states and other headaches.

[0867] Through their peripheral effects, H₃ receptor agonists andpartial agonists will be mainly indicated in the treatment ofrespiratoy, allergic or inflammatory conditions (asthma, bronchitis,rhinitis, tracheitis, and the like), cardiac conditions (myocardialdysfunction and infarction), gastrointestinal conditions as a result oftheir antisecretory and anti-inflammatory actions (gastric and duodenalulcers, ulcerative colitis, Crohn's disease, irritable bowel, faecalincontinence, and the like), conditions of the urogenital system(cystitis, metritis, premenstrual syndrome, prostatic inflammations,urinary incontinence, genital disorders) and conditions of the cutaneoussystem (urticaria, itching). The anti-inflammatory and analgesic effectmay usefully be turned to good account in the treatment of arthritis andother rheumatic conditions, conjunctivitis and other ocularinflammations, and sialorrhoea.

[0868] Compounds which are histamine H₃ receptor agonists or partialagonists are advantageously used as active principle of medicinalproducts, in particular having mild sedative, antisecretory,anti-inflammatory, steep-regulating and anticonvulsant effects,regulatory effects on hypothalamohypophyseal secretion, anti-depressanteffects, modulatory effects on cerebral circulation, modulatory effectson the immune system, and anti-allergic and antimigraine effects.

[0869] Hence the present invention also relates to pharmaceuticalcompositions which contain as active principle a therapeuticallyeffective amount of one of the agonist or partial agonist compounds offormule (A).

[0870] The present invention also relates to medicaments having theabove-mentioned effects comprising as active ingredient, atherapeutically effective amount of a compound of formula (A).

[0871] The present invention relates more particularly to suchmedicaments containing a compound of formula (I) to (XVIII).

[0872] The present invention also relates to pharmaceutical compositionscontaining as active ingredient, a therapeutically effective amount of acompound (A) together with a pharmaceutically acceptable vehicle orexcipient.

[0873] The invention is directed to such pharmaceutical compositionscontaining as active-ingredient, a compound of formula (I) to (XVIII).

[0874] The medicaments or pharmaceutical compositions according to theinvention can be administered via oral, parenteral or topical routes,the active ingredient being combined with a therapeutically suitableexcipient or vehicle.

[0875] According to the invention, oral administration is advantageouslyused.

[0876] Another subject of the present invention is the use of thecompounds of formula (A) for the preparation of H₃-antagonist and/oragonist medicaments according to the above-mentioned forms.

[0877] The invention further relates to the use of the compounds offormula (A) for preparing medicaments having the pre-cited effects.

[0878] The invention also concerns the use of a compound of formula (I)to (XVIII).

[0879] Still another subject of the invention is a method for thetreatment of precited ailments comprising administering atherapeutically effective dose of a compound (I), optionally incombination with a therapeutically acceptable vehicle or excipient.

[0880] The invention is also directed to such a method comprisingadministering a therapeutically effective dose of a compound of formula(I) to (XVIII).

[0881] For each of the above-indications, the amount of the activeingredient will depend upon the condition of the patient.

[0882] However, a suitable effective dose will be in general in therange of from 10 to 500 mg per day and of from 1 to 10 mg/day forparticularly active compounds.

[0883] These doses are given on the basis of the compound and should beadapted for the salts, hydrates or hydrated salts thereof.

[0884] The invention is now illustrated by the following examples.

EXAMPLES

[0885] The structure of the synthesized compounds and their method ofpreparation as well as their melting point, recrystalisation solvant andelemental analysis are summarized in the following Table I: TABLE 1 NFORMULA STRUCTURE NAME mp (recryst. solv) analysis (calc.) method  1

143-145° C. (absolute ethanol) C: 64.06 (64.07) H: 8.09 (8.16) N: 4.14(4.15) A  2

153-155° C. (absolute ethanol) C: 63.06 (63.14) H: 7.78 (7.79) N: 4.42(4.33) A  3

122-124° C. (absolute ethanol) C: 61.74 (61.72) H: 8.24 (8.09) N: 4.52(4.50) A  4

166-168° C. (absolute ethanol) C: 60.10 (60.16) H: 7.45 (7.31) N: 4.08(4.13) A  5

132-134° C. (absolute ethanol) C: 64.70 (64.93) H: 8.34 (8.32) N: 3.85(3.99) A  6

90-91° C. (isopropyl alcohol) C: 63.60 (63.69) H: 8.81 (8.61) N: 3.97(4.13) B  7

80-83° C. (isopropyl alcohol) C: 64.15 (63.98) H: 8.42 (8.17) N: 3.97(3.89) B  8

165-166° C. (absolute ethanol) C: 66.27 (66.46) H: 8.94 (8.76) N: 3.72(3.69) B  9

151-152° C. (absolute ethanol) C: 64.87 (64.93) H: 8.41 (8.32) N: 4.01(3.99) B  10

140-141° C. (isopropyl alcohol) C: 65.35 (64.93) H: 8.49 (8.32) N: 4.00(3.99) B  11

186-188° C. (absolute ethanol) C: 59.78 (59.99) H: 7.47 (7.42) N: 7.35(7.36) B  12

154-155° C. (absolute ethanol) C: 65.16 (65.25) H: 8.61 (8.47) N: 3.66(3.79) B  13

154-155° C. (isopropyl alcohol) C: 65.62 (65.73) H: 8.64 (8.55) N: 3.63(3.83) B  14

135-136° C. (acetone) C: 69.18 (69.32) H: 9.79 (9.70) N: 4.28 (4.49) B 15

149-150° C. (absolute ethanol) C: 61.16 (61.60) H: 7.76 (7.63) N: 3.40(3.42) B  16

117-118° C. (isopropyl alcohol) C: 61.54 (61.60) H: 7.87 (7.63) N: 3.29(3.42) B  17

177-179° C. (methanol) C: 64.19 (64.46) H: 7.49 (7.51) N: 4.25 (4.18) B 18

145-147° C. (absolute ethanol) C: 54.89 (54.89) H: 6.68 (6.61) N: 7.41(7.53) C  19

139-141° C. (absolute ethanol) C: 57.00 (57.06) H: 6.63 (6.76) N: 3.79(3.91) Cl: 10.24 (9.91) C  20

115-116° C. (absolute ethanol) C: 61.22 (61.17) H: 7.72 (7.70) N: 4.03(3.96) C  21

138-140° C. (absolute ethanol) C: 64.05 (64.07) H: 8.00 (8.07) N: 4.10(4.15) C  22

129-130° C. (absolute ethanol) C: 61.24 (61.16) H: 6.81 (6.82) N: 7.95(7.84) C  23

166-167° C. (methanol) C: 67.42 (67.54) H: 7.26 (7.29) N: 3.66 (3.75) C 24

160-163° C. (methanol) C: 65.12 (65.22) H: 7.17 (7.00) N: 3.52 (3.54) C 25

131-132° C. (absolute ethanol) C: 56.94 (57.06) H: 6.67 (6.76) N: 3.74(3.91) Cl: 9.64 (9.91) C  26

189-190° C. (methanol) C: 69.16 (69.15) H: 7.39 (7.32) N: 3.39 (3.51) C 27

131-132° C. (absolute ethanol) C: 66.73 (66.82) H: 8.37 (8.28) N: 3.68(3.71) C  28

155-157° C. (absolute ethanol) C: 68.40 (68.22) H: 7.04 (7.21) N: 3.45(3.43) C  29

140-141° C. (absolute ethanol) C: 63.45 (63.54) H: 7.26 (7.21) N: 4.26(4.36) B  30

148-149° C. (absolute ethanol) C: 66.99 (66.82) H: 8.47 (8.28) N: 3.72(3.71) C  31

143-144° C. (absolute ethanol) C: 62.25 (62.12) H: 7.46 (7.49) N: 4.49(4.53) C  32

146-147° C. (absolute ethanol) C: 63.06 (63.10) H: 8.03 (7.91) N: 4.32(4.04) C  33

150-152° C. (absolute ethanol) C: 59.52 (59.29) H: 7.44 (7.29) N: 4.06(4.02) C  34

114-116° C. (absolute ethanol) C: 59.24 (59.05) H: 7.16 (7.12) N: 4.16(4.30) S: 9.79 (9.85) C  35

169-170° C. (absolute ethanol) C: 60.98 (61.00) H: 7.14 (7.17) N: 4.64(4.74) C  36

130-131° C. (absolute ethanol) C: 55.30 (55.43) H: 6.55 (6.57) N: 7.49(7.60) C  37

149-150° C. (absolute ethanol) C: 59.52 (59.81) H: 7.12 (7.09) N: 4.05(4.10) C  38

148-149° C. (absolute ethanol) C: 57.32 (57.55) H: 7.19 (7.12) N: 6.89(7.07) C  39

130-134° C. (absolute ethanol) C: 62.43 (62.45) H: 7.41 (7.45) N: 3.75(3.83) D  40

120-122° C. (absolute ethanol) C: 52.49 (52.72) H: 6.74 (6.50) N: 6.32(6.40) E₁  41

119-120° C. (absolute ethanol) C: 61.95 (62.05) H: 6.88 (6.94) N: 8.00(8.04) C  42

160-161° C. (absolute ethanol/ methanol 1:1) C: 52.46 (52.63) H: 6.49(6.48) N: 8.10 (8.12) F  43

148-150° C. (absolute ethanol) C: 59.40 (59.62) H: 6.82 (6.88) N: 8.60(8.69) F  44

141-142° C. (absolute ethanol) C: 67.17 (67.43) H: 6.80 (6.84) N: 3.18(3.28) D  45

177-178° C. (absolute ethanol) C: 67.77 (68.01) H: 7.09 (7.08) N: 3.26(3.17) D  46

108-110° C. (absolute ethanol) C: 59.30 (59.30) H: 7.47 (7.29) N: 4.18(4.02) F  47

142-144° C. (absolute ethanol) C: 59.67 (59.99) H: 7.55 (7.42) N: 7.25(7.36) C  48

135-136° C. (absolute ethanol) C: 66.49 (66.49) H: 7.05 (7.04) N: 3.24(3.37) D  49

176-178° C. (absolute ethanol) C: 64.56 (64.38) H: 6.89 (6.74) N: 6.26(6.20) E₂  50

102-104° C. (absolute ethanol) C: 61.89 (62.11) H: 7.94 (7.96) N: 3.77(3.81) G  51

120-122° C. (absolute ethanol) C: 61.56 (61.70) H: 7.54 (7.48) N: 7.87(7.99) H  52

115-116° C. (absolute ethanol) C: 62.62 (62.97) H: 7.20 (7.23) N: 7.76(7.73) H  53

148-149° C. (absolute ethanol) C: 59.68 (59.62) H: 6.76 (6.88) N: 8.57(8.69) H  54

124-125° C. (absolute ethanol) C: 58.15 (58.43) H: 6.30 (6.54) N: 8.95(9.09) H  55

166-167° C. (absolute ethanol/ methanol 1:1) C: 57.01 (57.14) H: 6.02(6.16) N: 9.46 (9.52) H  56

143-145° C. (absolute ethanol) C: 60.80 (60.70) H: 7.11 (7.19) N: 8.22(8.33) H  57

134-136° C. (absolute ethanol) C: 63.38 (63.47) H: 8.11 (7.99) N: 7.29(7.40) H  58

163-165° C. (absolute ethanol) C: 58.95 (59.08) H: 6.23 (6.18) N: 8.43(8.51) H  59

151-153° C. (absolute ethanol) C: 60.62 (60.61) H: 6.66 (6.57) N: 8.25(8.27) H  60

124-125° C. (absolute ethanol) C: 61.62 (61.60) H: 6.94 (6.88) N: 7.87(7.94) H  61

110-112° C. (absolute ethanol) C: 62.90 (62.62) H: 7.76 (7.74) N: 7.61(7.69) H  62

127-128° C. (absolute ethanol) C: 61.57 (61.70) H: 7.57 (7.48) N: 7.91(7.99) H  63

33-36° C. (isopropyl alcohol) C: 58.15 (58.27) H: 8.15 (8.05) N: 4.21(4.00) G  64

99-100° C. (absolute ethanol) C: 57.26 (57.61) H: 7.47 (7.39) N: 7.72(7.90) J  65

159-160° C. (absolute ethanol) C: 61.18 (61.52) H: 7.11 (7.17) N: 3.96(3.99) K  66

143-144° C. (absolute ethanol) C: 62.11 (62.45) H: 7.41 (7.45) N: 3.79(3.83) K  67

171-172° C. (absolute ethanol) C: 63.06 (63.31) H: 7.44 (7.70) N: 3.64(3.69) K  68

160-161° C. (absolute ethanol) C: 62.47 (62.45) H: 7.46 (7.45) N: 3.77(3.83) K  69

148-149° C. (absolute ethanol) C: 62.54 (62.45) H: 7.51 (7.45) N: 3.79(3.83) L  70

174-175° C. (absolute ethanol) C: 63.22 (63.31) H: 7.60 (7.70) N: 3.64(3.69) K  71

152-153° C. (absolute ethanol) C: 60.23 (60.52) H: 6.81 (6.87) N: 4.15(4.15) L  72

121-122° C. (absolute ethanol) C: 63.02 (63.31) H: 7.73 (7.70) N: 3.66(3.69) L  73

118-120° C. (absolute ethanol) C: 57.27 (57.28) H: 7.00 (7.08) N: 3.47(3.52) L  74

138-139° C. (absolute ethanol) C: 63.09 (63.31) H: 7.78 (7.70) N: 3.75(3.69) L  75

143-144° C. (absolute ethanol) C: 61.21 (61.00) H: 6.25 (6.52) N: 4.00(3.91) K  76

177-179° C. (absolute ethanol) C: 63.10 (63.21) H: 7.28 (7.15) N: 3.61(3.67) L  77

149-151° C. (absolute ethanol) C: 61.72 (61.59) H: 7.59 (7.32) N: 3.74(3.74) M  78

200-202° C. (absolute ethanol/ diethyl ether 1:1) C: 64.57 (64.79) H:8.02 (7.88) N: 9.30 (9.44) N  79

171-173° C. (absolute ethanol/ diethyl ether 1:1) C: 64.87 (65.18) H:8.01 (7.86) N: 9.40 (9.50) N  80

148-150° C. (absolute ethanol) C: 62.20 (62.45) H: 7.46 (7.45) N: 3.73(3.83) M  81

148-150° C. (acetone) C: 66.10 (66.34) H: 8.92 (8.66) N: 4.16 (4.30) O 82

157-159° C. (absolute ethanol/ diethyl ether 1:4) C: 59.13 (59.40) H:6.60 (6.81) N: 8.94 (9.24) L  83

172-174° C. (absolute ethanol) C: 55.45 (55.43) H: 6.53 (6.57) N: 7.58(7.60) N  84

177-180° C. (absolute ethanol/ diethyl ether 1:5) C: 64.96 (65.18) H:7.79 (7.86) N: 9.44 (9.50) N  85

151-153° C. (absolute ethanol) C: 55.38 (55.43) H: 6.57 (6.57) N: 7.40(7.60) N  86

119-121° C. (absolute ethanol) C: 54.52 (54.74) H: 6.55 (6.46) N: 7.19(7.42) N  87

180-1825° C. (absolute ethanol/ diethyl ether 1:5) C: 58.52 (58.26) H:8.20 (8.17) N: 7.90 (7.99) N  88

135-136° C. (methanol/absolute ethanol 1:1) C: 63.34 (63.31) H: 7.63(7.70) N: 3.65 (3.69) N  89

80-82° C. (absolute ethanol) C: 58.54 (58.57) H: 6.57 (6.65) N: 2.97(3.02) L  90

143-145° C. (absolute ethanol/ diethyl ether 1:1) C: 64.39 (64.33) H:7.78 (7.59) N: 3.36 (3.38) L  91

158-159° C. (absolute ethanol) C: 63.38 (63.37) H: 7.19 (7.43) N: 7.22(7.35) N  92

sticky oil (after removal of absolute ethanol) C: 59.89 (60.04) H: 7.39(7.42) N: 6.31 (6.37) N  93

161-163° C. (absolute ethanol) C: 62.73 (62.97) H: 7.28 (7.23) N: 7.64(7.73) N  94

163-165° C. (methanol/absolute ethanol 1:1) C: 62.43 (62.46) H: 7.67(7.58) N: 3.53 (3.61) N  95

92-94° C. (methanol/absolute ethanol 1:1) C: 63.01 (63.31) H: 7.79(7.70) N: 3.61 (3.69) N  96

144-145° C. (methanol/absolute ethanol 1:1) C: 62.95 (62.97) H: 8.13(8.19) N: 3.54 (3.67) P  97

182-183° C. (methanol/absolute ethanol 1:1) C: 62.64 (62.97) H: 8.31(8.19) N: 3.62 (3.67) P  98

151-153° C. (absolute ethanol/ diethyl ether 1:1) C: 62.91 (63.09) H:8.64 (8.59) N: 8.28 (8.17) J  99

179-181° C. (methanol/absolute ethanol 1:1) C: 61.86 (61.75) H: 7.81(7.90) N: 6.82 (6.86) Q 100

163-165° C. (absolute ethanol) C: 63.04 (62.97) H: 7.10 (7.23) N: 7.53(7.73) N 101

136-138° C. (absolute ethanol/ diethyl ether 1:1) C: 64.54 (64.59) H:7.70 (7.74) N: 3.44 (3.42) N 102

130-132° C. (absolute ethanol/ diethyl ether 1:1) C: 64.50 (64.33) H:7.82 (7.59) N: 3.33 (3.38) N 103

156-158° C. (methanol) C: 59.03 (58.85) H: 6.76 (6.86) N: 3.77 (3.81) L104

118-120° C. (absolute ethanol/ diethyl ether 1:3) C: 67.26 (67.38) H:7.83 (7.92) N: 3.08 (3.14) R 105

185-187° C. (absolute ethanol/ diethyl ether 1:3) C: 64.28 (64.30) H:8.77 (8.80) N: 7.80 (7.89) Q 106

105-107° C. (absolute ethanol/ diethyl ether 1:3) C: 65.25 (65.24) H:8.44 (8.44) N: 2.80 (2.82) S 107

157-160° C. (methanol) C: 59.92 (59.98) H: 8.00 (7.86) N: 6.74 (6.82) J108

175-177° C. (absolute ethanol) C: 49.52 (49.50) H: 5.62 (5.71) N: 3.50(3.61) L 109

148-151° C. (absolute ethanol) C: 54.14 (54.23) H: 6.26 (6.26) N: 7.88(7.91) L 110

149-153° C. (absolute ethanol) C: 51.58 (51.91) H: 6.80 (6.78) N: 6.84(6.73) L 111

131-134° C. (absolute ethanol) C: 64.68 (64.93) H: 8.50 (8.32) N: 3.96(3.99) L 112

133-136° C. (absolute ethanol) C: 64.67 (64.79) H: 8.47 (8.40) N: 3.76(3.74) L 113

121-124° C. (absolute ethanol) C: 63.46 (63.31) H: 8.36 (8.39) N: 3.92(3.89) L 114

148-151° C. (absolute ethanol) C: 62.65 (62.41) H: 7.88 (8.15) N: 4.42(4.04) L No Structure Synthesis 115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

No Structure Synthesis 137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

[0886] The following compounds can be prepared according to thesynthesis schemes: No. Structure Synthesis 171

scheme 7 N-(3-(N,N-Diethylamino)propyl)N′-phenylurea 172

scheme 7 N-Cyclohexylmethyl-N′-(3-piperidinopropyl)guanidine 173

scheme 12 N-(4-Bromobenzyl)-N′-(4-piperidinobutyl)sulphamide 174

scheme 12 3-Chloro-N-(4-piperidinobutyl)-N-methyl-benzene sulphonamide175

scheme 11 N-(4-Chlorobenzyl)-2-(4-piperidinomethyl)phenyl)ethan amidine176

scheme 9 1-(5-Cyclohexylpentanoyl)-1-4-bipiperidine 177

cis-1-(6-Cyclohexyl-3-hexen-1-yl)piperidine 178

trans-1-(6-Cyclohexyl-3-hexen-1-yl)piperidine 179

1-(6-Cyclohexyl-3-hexin-1-yl)piperidine 180

scheme 14 1-(2-(5,5-Dimethyl-1-hexin-1-yl)cyclopropyl)piperidine

[0887] Compounds 1 to 114 are prepared according to the followingprocedures:

[0888] Method A:

[0889] A solution of 1-bromo-5phenoxypentane (1.4 to 3.5 mmol) in tenequivalents of the suitable secondary amine was heated to refluxtemperature with stirring for 48 hours (compds. 1, 3 and 4), 24 hours(compd. 2) or 4 hours (compd. 5). After cooling, the excess base wasremoved under reduced pressure and the residue diluted with aqueoussodium hydroxide. The product was extracted with diethyl ether, theorganic extracts washed with water, dried over magnesium sulphate,filtered and concentrated under reduced pressure. The remaining oil wasconverted to oxalate salt by dissolving in a small amount of absoluteethanol and adding a solution of two equivalents oxalic acid in absoluteethanol. The precipitate formed was washed with diethyl ether andrecrystallised from absolute ethanol.

[0890] Method B:

[0891] A solution of 1-bromo-5phenoxypentane (0.9 to 1.7 mmol) and anexcess of the suitable secondary amine (2.3 to 10 equivalents) in 10 mlabsolute ethanol was heated to reflux temperature with stirring for 48hours (compd. 6) or 24 hours (compds. 7, 8, 9, 10, 11, 12&13, 14, 15,16, 17 and 29). After cooling, the solvent was removed under reducedpressure and the residue diluted with aqueous sodium hydroxide. Theproduct was extracted with diethyl ether, the organic extracts washedwith water, dried over magnesium sulphate, filtered and concentratedunder reduced pressure. The cis and trans isomers 12 and 13 wereseparated by column chromatography on silica gel eluting with a solventmixture of petroleum spirit (bp 60-80° C.), diethyl ether andtriethylamine in the ratio 66:33:1, and the eluent was removed underreduced pressure to leave an oil. Compounds 14 and 16 were purified bycolumn chromatography on silica gel eluting with diethyl ether andtriethylamine in the ratio 99:1, and the eluent was removed underreduced pressure to leave an oil. The oil was converted to oxalate salt(compds. 6, 7, 8, 9, 11, 12, 13, 15, 16, 17 and 29) by dissolving in asmall amount of absolute ethanol and adding a solution of twoequivalents of oxalic acid in absolute ethanol. If no precipitateappeared, diethyl ether was added to form a precipitate. The solid waswashed with diethyl ether and recrystallised from isopropyl alcohol(compds. 6, 7, 10, 13 and 16), absolute ethanol (compds. 8, 9, 11, 12,15 and 29) or methanol (compd. 17). The oil was converted tohydrochloride salt (compd. 14) by adding 2N HCl. The precipitate wasformed in a mixture of chloroform and diethyl ether (1:1) andrecrystallised from acetone.

[0892] Method C:

[0893] A solution of the suitable α-bromo-ω-aryloxy alkane (0.4 to 1.4mmol) or ω-bromoalkyl phenyl sulphide (1 mmol, compds. 33 and 34) and anexcess of pyrrolidine (10 to 15 equivalents) or 3-methylpiperidine (10equivalents, compd. 38) in 10 ml absolute ethanol was heated to refluxtemperature with stirring for 24 hours or 16 hours (compd. 47). Aftercooling, the solvent was removed under reduced pressure and the residuediluted with aqueous sodium hydroxide. The product was extracted withdiethyl ether, the organic extracts washed with water, dried overmagnesium sulphate, filtered and concentrated under reduced pressure.The remaining oil was converted to oxalate salt by dissolving in a smallamount of absolute ethanol and adding a solution of two equivalentsoxalic acid in absolute ethanol. If no precipitate appeared, diethylether was added to form a precipitate. The solid was washed with diethylether and recrystallised from absolute ethanol.

[0894] Method D:

[0895] A solution of the suitable 4′-(5-bromopentoxy)phenyl ketone (0.7to 1 mmol, compds. 39, 44 and 45) or 1-bromo,5-(4-phenoxyphenoxy)pentane (0.6 mmol, compd. 48) and an excess ofpyrrolidine (10 to 15 equivalents) in 10 ml absolute ethanol was heatedto reflux temperature with stirring for 16 hours (compds. 39, 44 and 48)or 24 hours (compd. 45). After cooling, the solvent was removed underreduced pressure and the residue diluted with aqueous sodium hydroxide.The product was extracted with chloroform (compds. 39, 45 and 48) ordichloromethane (compd. 44), the organic extracts dried over magnesiumsulphate, filtered and concentrated under reduced pressure. Theremaining oil was converted to oxalate salt by dissolving in a smallamount of absolute ethanol and adding a solution of two equivalentsoxalic acid in absolute ethanol. The precipitate was washed with diethylether and recrystallised from absolute ethanol (recrystallised twicefrom absolute ethanol in the case of compd. 39).

[0896] Method E:

[0897] 1. The oxalate 18 was prepared according to method C. A solutionof compound 18 (0.57 mmol) in 10 ml methanol and 10 ml absolute ethanolwas placed with 100 mg of palladium (5%) on carbon catalyst in atwo-neck round-bottom flask fitted with a balloon filled with hydrogen.The mixture was stirred vigorously at room temperature and the flask waspurged of air and filled with hydrogen. After 3 hours, the catalyst wasfiltered off on celite and the solvent removed under reduced pressure.The residual solid was converted to oxalate salt by dissolving inmethanol and adding a solution of oxalic acid (2 equivalents) inabsolute ethanol. Diethyl ether was added to form a precipitate. Theproduct was recrystallised from absolute ethanol.

[0898] 2. To a solution of compound 40 (0.35 mmol) in pyridinevigorously stirred at 0° C. was added dropwise a slight excess ofbenzoyl chloride (0.4 mmol). The stirring was allowed to continue 20minutes after the end of the addition after which the mixture was placedin the refrigerator overnight (16 hours). The solvent was removed underreduced pressure and the residue diluted with aqueous sodium hydroxide.The product was extracted with chloroform, the organic extracts driedover magnesium sulphate, filtered and concentrated under reducedpressure. The remaining oil was converted to oxalate salt by dissolvingin a small amount of absolute ethanol and adding a solution of twoequivalents oxalic acid in absolute ethanol. The precipitate wasdissolved in methanol, filtered, and concentrated under reducedpressure. The solid was recrystallised from absolute ethanol

[0899] Method F:

[0900] In a three-neck flask kept under nitrogen was placed a solutionof the suitable phenol (1.6 mmol), 3-(diethylamino)propanol (1.5 mmol),and triphenyl phosphine (1.9 mmol) in 10 ml freshly distilledtetrahydrofuran. The mixture was stirred and cooled to 0° C. with an iceand salt bath. A solution of diisopropyl azodicarboxylate (2 mmol) in 10ml tetrahydrofuran was added very slowly (typically over 40 minutes) andthe mixture was allowed to warm to room temperature after which it wasstirred overnight at room temperature (16 hours). The solvent was thenremoved under reduced pressure, the residue dissolved in ethyl acetate(20 ml) and the product extracted with 2N HCl (2×10 ml). The aqueoussolution was neutralised with sodium hydroxide and the product extractedwith dichloromethane. After drying over magnesium sulphate andfiltration, the solvent was removed under reduced pressure. The residuewas converted to oxalate salt by dissolving in a small amount ofabsolute ethanol and adding a solution of two equivalents oxalic acid inabsolute ethanol. If no precipitate appeared, diethyl ether was added toform a precipitate. The solid was washed with diethyl ether andrecrystallised from absolute ethanol (compds. 43 and 46) or from a 1:1mixture of methanol and absolute ethanol (compd. 42).

[0901] Method G:

[0902] A solution of the free base of compound 39 (0.6 mmol) or compound46 (0.8 mmol) in 20 ml dry diethyl ether was added dropwise to a stirredsuspension of lithium aluminium hydride (0.6 or 0.8 mmol) in 20 ml drydiethyl ether kept under nitrogen. The mixture was stirred at roomtemperature under nitrogen for two hours. Ice-cold water was carefullyadded and the organic layer decanted. The aqueous phase was extractedwith diethyl ether. The combined organic solutions were dried overmagnesium sulphate, filtered and concentrated under reduced pressure toleave a yellow oil. The oil was converted to oxalate salt by dissolvingin a small amount of absolute ethanol and adding a solution of twoequivalents oxalic acid in absolute ethanol. The precipitate was washedwith diethyl ether and recrystallised from absolute ethanol (compd 50)or from isopropyl alcohol, giving a very hygroscopic solid (compd. 63).

[0903] Method H:

[0904] A solution of the suitable α-bromo-ω-(4-cyanophenoxy) alkane (0.5to 0.7 mmol) and an excess of the suitable secondary amine (8 to 12equivalents) in 10 ml absolute ethanol was heated to reflux temperaturewith stirring for 24 hours (compds. 54, 55, 57 and 60), 20 hours (compd.52), 16 hours (compds. 56, 58, 59 and 61) or 8 hours (compd. 51) or wasstirred at room temperature for 48 hours (compd. 53) or 24 hours (compd.60). After cooling, the solvent was removed under reduced pressure andthe residue diluted with aqueous sodium hydroxide. The product wasextracted with diethyl ether, the organic extracts washed with water,dried over magnesium sulphate, filtered and concentrated under reducedpressure. Compound 62 was purified by column chromatography on silicagel eluting with ethyl acetate, and concentrated under reduced pressure.For all the compounds of method H, the remaining oil was converted tooxalate salt by dissolving in a small amount of absolute ethanol andadding a solution of two equivalents oxalic acid in absolute ethanol. Ifno precipitate appeared, diethyl ether was added to form a precipitate.The solid was washed with diethyl ether and recrystallised from absoluteethanol (two recrystallisations were required for compds. 58 and 59) orfrom a 1:1 mixture of methanol and absolute ethanol (compd. 55).

[0905] Method J:

[0906] A solution of compound 46 (1 mmol) in 10 ml methanol was stirredat room temperature and a solution of hydroxylamine hydrochloride (2equivalents) in 2 ml water was added. The mixture was stirred at 50-70°C. in a water bath for 20 minutes. Methanol was removed under reducedpressure. The residue diluted with aqueous sodium hydroxide. The productwas extracted with diethyl ether, the organic extracts washed withwater, dried over magnesium sulphate, filtered and concentrated underreduced pressure. Compound 64 was purified by column chromatography onsilica gel eluting with ethyl acetate, and concentrated under reducedpressure. The remaining oil was converted to oxalate salt by dissolvingin a small amount of absolute ethanol and adding a solution of twoequivalents oxalic acid in absolute ethanol. Diethyl ether was added toform a precipitate. The solid was washed with diethyl ether andrecrystallised from absolute ethanol.

[0907] For example 98, the product was converted to the hydrochloridesalt by addition of 2N HCl. The salt was recrystallised from absoluteethanol/diethyl ether (1:1).

[0908] Method K:

[0909] A solution of 4′-(3-bromopropoxy)acetophenone (0.8 to 1.9 mmol)and an excess of the suitable piperidine (3 to 10 equivalents) in 10 mlabsolute ethanol was heated to reflux temperature with stirring for 16hours. After cooling, the solvent was removed under reduced pressure andthe residue diluted with aqueous sodium hydroxide. The product wasextracted with diethyl ether, the organic extracts washed with water,dried over magnesium sulphate, filtered and concentrated under reducedpressure. The cis and trans isomers 67 and 70 were separated by columnchromatography on silica gel eluting with a solvent mixture of diethylether, petroleum spirits (bp 60-80° C.) and triethylamine in the ratio66:33:1, and the eluent was removed under reduced pressure to leave anoil. Compound 75 was purified by column chromatography on silica geleluting with chloroform and methanol (1:1), and concentrated underreduced pressure. The remaining oil was converted to oxalate salt bydissolving in a small amount of absolute ethanol and adding a solutionof two equivalents of oxalic acid in absolute ethanol. If no precipitateappeared, diethyl ether was added to form a precipitate. The solid waswashed with diethyl ether and recrystallised from absolute ethanol.

[0910] Method L:

[0911] In a three-neck flask kept under nitrogen was placed a solutionof the suitable 4′-hydroxyphenyl ketone (0.9 to 3 mmol),3-(1-piperidinyl)propanol (0.9 to 3 mmol), and triphenyl phosphine (1 to3.5 mmol) in 10 ml freshly distilled tetrahydrofuran. The mixture wasstirred and cooled to 0° C. with an ice and salt bath. A solution ofdiethyl azodicarboxylate (1 to 3.6 mmol) in 10 ml tetrahydrofuran wasadded very slowly (typically over 40 minutes) and the mixture wasallowed to warm to room temperature after which it was stirred overnightat room temperature (16 hours). The solvent was then removed underreduced pressure, the residue dissolved in ethyl acetate (20 ml) and theproduct extracted with 2N HCl (2×10 ml). The aqueous solution wasneutralised with sodium hydroxide and the product extracted withdichloromethane. After drying over magnesium sulphate and filtration,the solvent was removed under reduced pressure. The crude product waspurified by column chromatography on silica gel eluting with diethylether containing 1% triethylamine, and concentrated under reducedpressure. The residue was converted to oxalate salt by dissolving in asmall amount of absolute ethanol and adding a solution of twoequivalents oxalic acid in absolute ethanol. If no precipitate appeared,diethyl ether was added to form a precipitate. The solid was washed withdiethyl ether and recrystallised from absolute ethanol.

[0912] For example 82, the amine was converted to the hydrochloride saltby addition of 2N HCl. The salt was recrystallised from absoluteethanol/diethyl ether (1:14).

[0913] Method M:

[0914] A solution of 3-(4-acetylphenoxy)-2-(R or S)-methylpropylpara-toluene sulfonate (0.55 to 0.66 mmol) and piperidine (5 to 6 mmol)in 10. ml absolute ethanol was stirred and heated under reflux for 2hours. After cooling, the solvent was removed under reduced pressure,the residue diluted with aqueous NaOH (10 ml) and the oil was extractedwith diethyl ether (3×10 ml). The combined extracts were dried overmagnesium sulfate, and the solvent removed under reduced pressure. Theyellow oil was purified by column chromatography on silica gel elutingwith a 1:1 mixture of chloroform and absolute ethanol (example 80).After concentration, the oil was dissolved in about 2 ml absoluteethanol and a solution of oxalic acid (1 to 1.1 mmol) in 2 ml absoluteethanol was added. The precipitate was recrystallised from absoluteethanol.

[0915] Method N:

[0916] A solution of 1-bromo-3-(4-substitutedphenoxy)propane (0.4 to 2mmol) and the suitably substituted piperidine (2.5 to 8 mmol) in 10 mlabsolute ethanol was stirred and heated under reflux for 6 to 24 hours.After cooling, the solvent was removed under reduced pressure, theresidue diluted with aqueous NaOH (10 ml) and the oil was extracted withdiethyl ether (3×10 ml). The combined extracts were dried over magnesiumsulfate, and the solvent removed under reduced pressure. The residualoil was dissolved in about 5 ml diethyl ether and a solution of HCl in10 ml diethyl ether was added. The precipitate was recrystallised from a1:1 or 1:5 mixture of absolute ethanol and diethyl ether (examples 78,79, 84, 87). The oil was purified by column chromatography on silica geleluting with a mixture of 33% petroleum ether (60-80° C.), 66% diethylether and 1% triethylamine (examples 101 and 102) or with 99% diethylether and 1 % triethylamine (examples 88, 94 and 95) and concentrated.The residual oil was dissolved in about 5 ml absolute ethanol and asolution of oxalic acid (1 to 1.6 mmol) in 5 ml absolute ethanol wasadded. The precipitate was recrystallised from absolute ethanol or froma 1:1 mixture of methanol and absolute ethanol (examples 83, 85, 86, 91,93, 100, 101 and 102). The product was obtained as a sticky oil afterremoval of absolute ethanol (example 92).

[0917] Method O:

[0918] A mixture of 4-(4-hydroxyphenyl)-2-butanone (200 mg, 1.2 mmol),3-chloropropyl piperidine hydrochloride (200 mg, 1 mmol) and potassiumcarbonate (830 mg, 6 mmol) in 10 ml absolute ethanol was stirred andheated under reflux for 8 hours. After cooling, the reaction mixture wasfiltered and concentrated under reduced pressure. The residue wasdiluted with aqueous sodium hydroxide and extracted with diethyl ether(3×10 ml). The combined extracts were dried over magnesium sulfate, andthe solvent removed under reduced pressure. The free base was dissolvedin diethyl ether and a solution of HCl in diethyl ether was added. Theprecipitate was recrystallised from acetone.

[0919] Method P:

[0920] A solution of the ketone (0.4 mmol) in 10 ml methanol was stirredat 0° C. in an ice-bath. To this solution was added portionwise NaBH₄ (1mmol). The mixture was left to stir at room temperature for 16 hours.The solvent was removed, water (10 ml) was added to the residue and theproduct was extracted with chloroform (4×10 ml). The combined extractswere dried over magnesium sulfate, and the solvent removed under reducedpressure. The free base was dissolved in absolute ethanol (5 ml) and asolution of oxalic acid (1 mmol) in 5 ml absolute ethanol was added. Theprecipitate was recrystallised from absolute ethanol.

[0921] Method Q:

[0922] Similar to method J using methoxylamine in place ofhydroxylamine. For example 105, the product was converted to thehydrochloride salt by addition of 2N HCl. The salt was recrystallisedfrom absolute ethanol/diethyl ether (1:3).

[0923] Method R:

[0924] Similar to method P. The reduced product was converted to thehydrochloride salt by addition of 2N HCl. Then, the product wasconverted to the free base by addition of 10% aqueous NaOH. Then, theproduct was converted to the para-toluene sulfonate by addition of asolution of para-toluene sulfonic acid (1 mmol) in 5 ml absoluteethanol. The precipitate was recrystallised from absoluteethanol/diethyl ether (1:3).

[0925] Method S:

[0926] Similar to method P. The reduced product was converted to thepara-toluene sulfonate by addition of a solution of para-toluenesulfonic acid (1 mmol) in 5 ml absolute ethanol. The precipitate wasrecrystallised from absolute ethanol/diethyl ether (1:3).

[0927] Intermediates:

[0928] (4-hydroxyphenyl)cyclopropyl ketone, intermediate for examples76, 101 and 102.

[0929] S. N. Rastogi et al. J. Med. Chem. 15, 286-291 (1972)

[0930] 4′-(3-hydroxy-2-(R)-methylpropoxy)acetophenone and4′-(3-hydroxy-2-(S)-methylpropoxy) acetophenone, intermediates forexamples 77 and 80.

[0931] A mixture of 4′-hydroxyacetophenone (1.3 to 2.8 mmol),3-bromo-2-(R or S)-methyl-1-propanol (1.3 to 2.6 mmol) and potassiumcarbonate (1.7 to 3.6 mmol) in acetone (20 ml) was stirred and heatedunder reflux for 24 hours. The suspension was filtered hot and thesolvent removed under reduced pressure to leave an oil that was purifiedby column chromatography on silica gel eluting with a mixture of diethylether and petroleum ether (60-80° C.). After concentration, a colourlessoil was obtained.

[0932] NMR: 7.91 (m, 2H); 6.92 (m, 2H); 4.01 (m, 2H); 3.71 (br, 2H);2.54 (s, 3H); 2.21 (m, 1H); 2.10 (br, 1H); 1.06 (d, 3H)

[0933] NMR: 7.91 (m, 2H); 6.93 (m, 2H); 4.01 (m, 2H); 3.71 (br, 2H);2.55 (s, 3H); 2.23 (m, 1H); 2.09 (br, 1H); 1.06 (d, 3H)

[0934] 3-(4-acetylphenoxy)-2-(S)-methylpropyl para-toluene sulfonate and3-(4-acetylphenoxy)-2-(R)-methylpropyl para-toluene sulfonate,intermediates for examples 77 and 80.

[0935] A solution of 4′-(3-hydroxy-2-(R or S)-methylpropoxy)acetophenone(0.7 to 1.2 mmol) in pyridine (5 ml) was stirred at 0° C. andpara-toluene sulfonyl chloride (1 to 1.6 mmol) was added portionwise.The mixture was subsequently placed in the refrigerator overnight. Thesolvent was then removed under reduced pressure and the residue purifiedby column chromatography on silica gel eluting with a mixture of 50%diethyl ether and 50% petroleum ether 60-80° C. After concentration, acolourless oil was obtained. In the case of the R-isomer, the oil formeda white solid that was recrystallised from absolute ethanol.

[0936] NMR: 7.91 (m, 2H); 7.74 (m, 2H); 7.23 (m, 2H); 6.79 (m, 2H); 4.11(m, 2H); 3.87 (m, 2H); 2.57 (s, 3H); 2.38 (s, 3H); 2.33 (m, 1H); 1.07(d, 3H)

[0937] NMR: 7.88 (m, 2H); 7.71 (m, 2H); 7.21 (m, 2H); 6.75 (m, 2H); 4.07(m, 2H); 3.83 (m, 2H); 2.53 (s, 3H); 2.34 (s, 3H); 2.30 (m, 1 H); 1.04(d, 3H)

[0938] 1-bromo-3-(4-nitrophenoxy)propane, intermediate for examples 83,85 and 86. J. N. Ashley et al. J. Chem. Soc. 3298-3304 (1958)

[0939] 1-bromo-3-(4-propionylphenoxy)propane, intermediate for examples88, 94 and 95.

[0940] To a stirred and heated mixture of 1,3-dibromopropane (80 mmol)and potassium carbonate (50 mmol) in acetone (200 ml) was added dropwisea solution of the hydroxy ketone (40 mmol) in acetone (80 ml). Thereaction was allowed to continue overnight. The mixture was filtered hotand the solvent removed under reduced pressure to leave an oil that wasdissolved in ethyl acetate. Addition of petroleum spirit (60-80° C.)formed a precipitate. The solid was filtered and dried under reducedpressure.

[0941] NMR: 7.96 (m, 2H); 6.93 (m, 2H); 4.18 (t, 2H); 3.62 (t, 2H);2.96. (q, 2H); 2.34 (m, 2H); 1.22 (t, 3H)

[0942] (4-hydroxyphenyl)cyclobutyl ketone and(4-hydroxyphenyl)cyclopentyl ketone, intermediates for examples 89 and90.

[0943] A mixture of cyclobutylcarbonyl chloride (5 mmol) orcyclopentylcarbonyl chloride (7 mmol) and aluminium chloride (15 mmol)in dry dichloromethane (40 ml) was stirred at 0° C. and a solution ofphenol (8 mmol) in dry dichloromethane (20 ml) was added dropwise. themixture was then stirred and heated under reflux for 3 hours. Aftercooling to 0° C., water was added with vigorous stirring. The organiclayer was decanted off, dried over magnesium sulfate and concentrated.The crude product was purified by column chromatography on silica geleluting with petroleum ether/diethyl ether (2:1).

[0944] NMR: 7.72 (m, 2H); 6.80 (m, 2H); 3.95 (m, 1H); 2.45 (m, 2H); 2.15(m, 4H)

[0945] NMR: 7.92 (m, 2H); 7.25 (s, 1H); 6.92 (m, 2H); 3.70 (m, 1H); 2.00(m, 4H); 1.75 (m, 4H)

[0946] 1-bromo-3-(4-cyclopropanecarbonylphenoxy)propane, intermediatefor examples 101 and 102.

[0947] To a stirred and heated mixture of 1,3-dibromopropane (5 mmol)and potassium carbonate (3.4 mmol) in acetone (40 ml) was added dropwisea solution of 4-cyclopropanecarbonylphenol (5 mmol) in acetone (20 ml).The reaction was allowed to continue overnight. The mixture was filteredhot and the solvent removed under reduced pressure to leave an oil. Theoil was purified by column chromatography on silica gel eluting withpetroleum ether/ethyl acetate (15:1).

[0948] 4-(N,N-dimethylsulfonamido)phenol, intermediate for example 110.N. Eliel J. Org. Chem. 20, 1657-1660 (1955)

[0949] Compounds 115 to 170 are prepared according to the followingprocedures:

Example 115

[0950] 3,3-Dimethylbutyl 3-piperidinopropyl ether

[0951] Sodium 3-piperidinopropanolate (5 mmol), 5 mmol of3,3-dimethylbutyl chloride, a catalytic amount of tetrabutylammoniumiodide, and 0.5 mmol of 15-crown-5 in 10 ml of dry dimethyl sulfoxidewere refluxed for 12 hours. Water was added, and it was extracted withdiethyl ether. The organic layer was purified by column chromatographyon silica gel (eluent: methylene chloride/methanol (90/10), ammoniaatmosphere). The solvent was removed under reduced pressure and theresidue crystallized with oxalic acid from diethyl ether/ethanol. SF:C₁₄H₂₉NO × 1.1 C₂H₂O₄ (326.4)    mp: 143° C. CHN analysis calculated: C59.6 H 9.63 N 4.29 found: C 59.7 H 9.61 N 4.30

Example 116

[0952] 3-Phenylpropyl 3-piperidinopropyl ether

[0953] Sodium 3-piperidinopropanolate (20 mmol), 20 mmol of3-phenylpropyl bromide, and 0.5 mmol of 15-crown-5 in 30 ml of drytoluene were refluxed for 4 hours. The solvent was evaporated and theresidue purified by column chromatography on silica gel (eluent:methylene chloride/methanol/aqueous ammonia (90/10/0.5)). After removingthe solvent under reduced pressure the residue was crystallized withoxalic acid from diethyl ether/ethanol. SF: C₁₇H₂₇NO × C₂H₂O₄(351.4)    mp: 125° C. CHN analysis calculated: C 64.9 H 8.32 N 3.99found: C 64.9 H 8.13 N 4.02

Example 117

[0954] 3-(4-Chlorophenyl)propyl 3-piperidinopropyl ether

[0955] Sodium 3-piperidinopropanolate (20 mmol), 7 mmol of3-(4-chlorophenyl)propyl-mesylate, and 0.5 mmol of 15-crown-5 in 30 mlof dry toluene were refluxed for 4 hours. The solvent was evaporated andthe residue purified by column chromatography on silica gel (eluent:methylene chloride/methanol (90/10)). After removing the solvent underreduced pressure the residue was crystallized with oxalic acid fromdiethyl ether/ethanol. SF: C₁₇H₂₆NOCl × C₂H₂O₄ (385.9)    mp: 147° C.CHN analysis calculated: C 59.1 H 7.31 N 3.63 found: C 59.0 H 7.34 N3.60

Example 118

[0956] 2-Benzothiazolyl 3-piperidinopropyl ether

[0957] Sodium 3-piperidinopropanolate (5 mmol) and 5 mmol of2-chlorobenzothiazole in 20 ml of dry tetrahydrofurane were refluxed for12 hours. The suspension was filtered and the solvent evaporated underreduced pressure. The product was crystallized with oxalic acid fromdiethyl ether/ethanol. SF: C₁₅H₂₀N₂OS × C₂H₂O₄ (366.4)    mp:178.2-178.8° C. CHN analysis calculated: C 55.7 H 6.05 N 7.64 found: C55.6 H 6.03 N 7.51

Example 119

[0958] N-Phenyl-3-piperidinopropyl carbamate

[0959] 3-Piperidinopropanol hydrochloride (10 mmol) and 10 mmol ofphenyl isocyanate in 40 ml of dry acetonitrile were refluxed for 3hours. The solvent was evaporated, and then the residue wasrecrystallized in dry ethanol. SF: C₁₅H₂₂N₂O₂ × HCl × 0.1 H₂O(300.6)    mp: 169-170° C. CHN analysis calculated: C 59.9 H 7.78 N 9.32found: C 59.9 H 7.64 N 9.05

Example 120

[0960] N-Pentyl-3-piperidinopropyl carbamate

[0961] 3-Piperidinopropanol hydrochloride (4 mmol) and 4 mmol of pentylisocyanate in 20 ml of dry acetonitrile were refluxed for 3 hours. Thesolvent was evaporated and the residue purified by column chromatographyon silica gel (eluent: methylene chloride/methanol/aqueous ammonia(90/10/0.5)). After removing the solvent under reduced pressure theresidue was crystallized with hydrochloric acid in 2-propanol. SF:C₁₄H₂₈N₂O₂ × HCl × 0.5 H₂O (301.9)    mp: 88-89° C. CHN analysiscalculated: C 55.7 H 10.0 N 9.28 found: C 55.7 H 9.84 N 9.18

Example 121

[0962] (S)-(+)-N-[2-(3,3-Dimethyl)butyl]-3-piperidinopropyl carbamate

[0963] 3-Piperidinopropanol hydrochloride (5 mmol) and 5 mmol of(S)-2-(3,3-dimethyl)butyl isocyanate in 10 ml of dry acetonitrile wererefluxed for 12 hours. The solvent was evaporated and the residuepurified by column chromatography on silica gel (eluent: methylenechloride/methanol (90/10), ammonia atmosphere). The solvent was removedand the residue crystallized with oxalic acid from diethylether/ethanol. SF: C₁₅H₃₀N₂O₂ × C₂H₂O₄ × 0.25 H₂O (365.0)    mp: 148° C.[α]_(D) ²³ = +10.4° (c = 0.495, Methanol) CHN analysis calculated: C56.0 H 8.98 N 7.68 found: C 56.0 H 9.01 N 7.64

Example 122

[0964] N-(4-Chlorobenzyl)-S-(3-piperidinopropyl) isothiourea

[0965] 4-Chlorobenzylamine (10 mmol) was added dropwise to 10 mmol ofbenzoylisothiocyanate dissolved in 20 ml of dry ether followed bystirring for 2 hours. The precipitated product was filtered off andcrystallized from ethyl acetate (Yield: 60%). Potassium carbonate (10mmol) in 30 ml of water was added dropwise to 5 mmol of the product in20 ml of ethanol and refluxed for 2 hours. The precipitated product wasfiltered off and crystallized from ethyl acetate/petroleum ether (Yield:65%). 3-Piperidinopropyl chloride hydrochloride (3 mmol), 3 mmol of theproduct, and a catalytic amount of potassium iodide were refluxed in 20ml of ethanol for 2 days. Subsequently the ethanol was evaporated andthe residue purified by column chromatography using methanol/ethylacetate (2/8) as eluent. After evaporation of the solvent, the productwas crystallized with hydrochloric acid from diethyl ether/ethanol. SF:C₁₆H₂₄CIN₃S × 2 HCl × H₂O (416.8)    mp: 104-107.5° C. CHN analysiscalculated: C 46.1 H 6.77 N 10.1 found: C 45.9 H 6.87 N 9.69

Example 123

[0966] N′-Cyclohexylthiocarbamoyl-N-1,4′-bipiperidine

[0967] 1,4′-Bipiperidine (5 mmol) in 10 ml of dry ether was addeddropwise to 5 mmol of cyclohexyl isothiocyanate in 30 ml of dry etherfollowed by stirring for 2 hours. Filtration gave a residue, which wasdissolved in ethanol and crystallized with oxalic acid.Recrystallization resulted in the pure product. SF: C₁₇H₃₁N₃S × H₂C₂O₄ ×0.25 H₂O (404.1)    mp: 225-226° C. CHN analysis calculated: C 56.5 H8.35 N 10.39 found: C 56.2 H 8.25 N 10.33

Example 124

[0968] N-Heptanoyl-1,4′-bipiperidine

[0969] 1,4′-Bipiperidine (10 mmol) in 5 ml of water was added dropwiseto a solution of 5 mmol of n-heptanoyl chloride in 20 ml of dioxane.After stirring for 15 minutes the solvent was evaporated under reducedpressure and the residue purified by column chromatography on silica gel(eluent: methylene chloride/methanol/aqueous ammonia (90/10/0.5)). Thesolvent was removed under reduced pressure, and the residue wascrystallized with oxalic acid. SF: C₁₇H₃₂N₂O × H₂C₂O₄ (370.5)    mp:131-132° C. CHN analysis calculated: C 61.6 H 9.25 N 7.56 found: C 61.6H 9.36 N 7.50

Example 125

[0970] 3-Cyclopentyl-N-(3-(1-pyrrolidinyl)propyl)propanamide

[0971] 3-Cyclopentyl propionylchloride (5 mmol) in 10 ml of dioxane wasadded dropwise to a solution of 10 mmol of 1-(3-aminopropyl)pyrrolidinein water. After stirring for 4 hours the solvent was evaporated underreduced pressure and the residue purified by column chromatography onsilica gel (eluent: methylene chloride/methanol/aqueous ammonia(90/10/1)). The solvent was removed under reduced pressure and theresidue was crystallized with oxalic acid from diethyl ether/ethanol.SF: C₁₇H₂₈N₂O × H₂C₂O₄ × 0.5 H₂O (351.2)   mp: 89.5° C. CHN analysiscalculated: C 58.1 H 8.83 N 7.97 found: C 58.1 H 8.76 N 7.87

Example 126

[0972] N-Cyclohexyl-N′-(1-pyrrolidinyl-3-propyl)urea

[0973] In an argon atmosphere 10 mmol of cyclohexylisocyanate was addedslowly to 10 mmol of 1-(3-aminopropyl)pyrrolidine in 10 ml ofacetonitrile. The product precipitated instantly as a pure white solid.The solvent was removed under reduced pressure and the product wascrystallized with oxalic acid from diethyl ether/ethanol. SF: C₁₄H₂₇N₃O× C₂H₂O₄ × 0.25 H₂O (347.7) Yield: 83% mp: 113.3° C. CHN analysiscalculated: C 56.0 H 8.45 N 12.2 found: C 55.6 H 8.27 N 12.0

Example 127

[0974] α-(4-Acetylphenoxy)-α′-piperidino p-xylol

[0975] Hydroxyacetophenone (2 mmol) and 5 mmol of K₂CO₃ were stirred in20 ml of acetone with 2 ml of DMF for 10 minutes. After addition of 3.5mmol of α,α′-dibromoxylol the reaction was stirred at ambienttemperature for 12 hours and after addition of 7 mmol of piperidine for1 hour under reflux. The solvent was evaporated under reduced pressure.The residue was suspended in water, extracted with methylene chloride.The combined organic extracts were crystallized with oxalic acid.Recrystallization resulted in the pure product. SF: C₂₁H₂₅NO₂ × C₂H₂O₄(413.5)   mp: 136-137° C. CHN analysis calculated: C 66.8 H 6.58 N 3.39found: C 66.7 H 6.70 N 3.40

Example 128

[0976] α-(4-Acetylphenoxy)-α′-(1-pyrrolidinyl) p-xylol

[0977] Hydroxyacetophenone (2 mmol) and 5 mmol of K₂CO₃ were stirred in20 ml of acetone with 2 ml of DMF for 10 minutes. After addition of 3.5mmol of α,α′-dibromoxylol the reaction was stirred at ambienttemperature for 12 hours and after addition of 7 mmol of pyrrolidine for1 hour under reflux. The solvent was evaporated under reduced pressure.The residue was suspended in water, extracted with methylene chloride.The combined organic extracts were crystallized with oxalic acid.Recrystallization resulted in the pure product. SF: C₂₀H₂₃NO₂ × C₂H₂O₄ ×0.25 H₂O (404.0)   mp: 136-137° C. CHN analysis calculated: C 65.4 H6.36 N 3.47 found: C 65.6 H 6.29 N 3.47

Example 129

[0978] α-(3-Phenylpropoxy)-α′-piperidino p-xylol

[0979] 4-(Piperidinomethyl)benzoic acid methyl ester (22 mmol) in drytetrahydrofurane was added dropwise to a suspension of 44 mmol oflithium aluminium hydride in 30 ml of dry tetrahydrofurane at 0° C.After refluxing for 2 hours a saturated solution of ammonium chloride inwater was added dropwise. After stirring for 12 hours at ambienttemperature the organic layer was isolated and the aqueous layerextracted with methylene chloride. The organic extracts were combinedand the solvent was evaporated under reduced pressure. The residue wascrystallized with maleic acid from diethyl ether/2-propanol (Yield:91%). Sodium 4-(piperidinomethyl)benzyl alcoholate (5 mmol) and 6 mmolof 3-phenylpropyl bromide in 10 ml of dry toluene were refluxed for 6hours. The solvent was evaporated under reduced pressure. The residuewas purified by rotatory chromatography on silica gel using methylenechloride/ammonia atmosphere as eluent. The product was crystallized withoxalic acid from diethyl ether/ethanol. SF: C₂₂H₂₉NO × C₂H₂O₄ × 0.5 H₂O(422.5)   mp: 104-105° C. CHN analysis calculated: C 68.2 H 7.63 N 3.32found: C 68.3 H 7.26 N 3.36

Example 130

[0980] 3-(4-Chlorobenzyl)-5-(2-piperidinoethyl)-1,2,4-oxadiazole

[0981] Hydroxylamine hydrochloride (20 mmol) was added dropwise to asolution of 20 mmol of sodium in 50 ml of methanol at 0° C. Afterstirring for 30 minutes at ambient temperature 10 mmol of 4-chlorobenzylcyanide was added dropwise at 0° C. After refluxing for 6 hours thesuspension was filtered and the solvent evaporated under reducedpressure. The residue was crystallized from diethyl ether (Yield: 41%).To a solution of 4 mmol of the product and 6 mmol of3-piperidinopropionic acid methyl ester in 15 ml of dry methanol 5 mmolof sodium in 20 ml of methanol was added dropwise at 0° C. Afterstirring for 1 hour under argon atmosphere followed by refluxing for 18hours the solvent was evaporated under reduced pressure. The residue wassuspended in DMF and stirred for 6 hours at 80° C. The solvent wasevaporated under reduced pressure. The residue was suspended in waterand extracted with methylene chloride. The residue of the organic layerwas purified by rotatory chromatography on silica gel using methylenechloride/ammonia atmosphere as eluent. The product was crystallized withoxalic acid from diethyl ether/ethanol. SF: C₁₆H₂₀ClN₃O × C₂H₂O₄(395.8)   mp: 152-154° C. CHN analysis calculated: C 54.6 H 5.60 N 10.6found: C 54.3 H 5.60 N 10.5

Example 131

[0982] 2-((2-Piperidinoethyl)amino)benzothiazole

[0983] 2-Chlorobenzothiazole (10 mmol), 10 mmol of2-piperidinoethanamine, and 30 mmol of triethylamine in 50 ml of dryethanol were refluxed for 6 hours. The product was crystallized withhydrochloric acid in 2-propanol and recrystallized in methanol. SF:C₁₄H₁₉N₃S × 2 HCl × 0.25 H₂O (338.8) Yield: 95% mp: 225° C. CHN analysiscalculated: C 49.6 H 6.40 N 12.4 found: C 49.5 H 6.49 N 12.3

Example 132

[0984] 5-Piperidinopentylamine

[0985] 5-Chlorovaleronitrile (10 mmol), 20 mmol of piperidine, 20 mmolof potassium carbonate and a catalytic amount of potassium iodide in 50ml of ethanol were refluxed for 6 hours. The solvent was removed underreduced pressure, the residue suspended in water and extracted withmethylene chloride. The organic layer was purified by columnchromatography on silica gel using methylene chloride/methanol/aqueousammonia (90/10/1) as eluent (Yield: 59%). The product was added dropwiseto a suspension of 25 mmol of lithium aluminium hydride in 25 ml of drytetrahydrofurane at 0° C. After refluxing for 1 hour 10 ml of asaturated solution of sodium/potassium tartrate in water was addeddropwise. The residue was filtered off and the filtrate purified bycolumn chromatography on silica gel using methylenechloride/methanol/aqueous ammonia (90/10/1) as eluent. The residue wascrystallized with hydrochloric acid from diethyl ether/2-propanol. SF:C₁₀H₂₂N₂ × 2 HCl × 0.5 H₂O (252.2)   mp: 187° C. CHN analysiscalculated: C 47.6 H 9.99 N 11.1 found: C 47.8 H 9.70 N 11.0

Example 133

[0986] 5-Nitro-2-(6-piperidinohexyl)pyridine

[0987] 6-Aminohexanol (15 mmol), 15 mmol of 2-chloro-5-nitropyridine, 5ml of triethylamine, and a catalytic amount of potassium iodide wererefluxed in 30 ml of ethanol for 12 hours. The solvent was evaporated,and the residue was purified by column chromatography on silica gel(eluent: methylene chloride/methanol (95/5), ammonia atmosphere). Thesolvent was removed under reduced pressure (Yield: 66%). The product (5mmol) was dissolved in tetrahydrofurane, stirred at 0° C. and 10 mmol ofthionyl chloride was added dropwise. After 1 hour at ambient temperaturethe mixture was warmed to 60° C. for 2 hours. The solvent and the excessof thionyl chloride were evaporated. The oily residue was crystallizedwith hydrochloric acid from diethyl ether/ethanol (Yield: 95%). Theproduct (5 mmol), 10 mmol of piperidine, 15 mmol of potassium carbonate,and a catalytic amount of potassium iodide were refluxed in 30 ml ofethanol for 12 hours. The solvent was evaporated and the residuepurified by column chromatography (eluent: methylene chloride/methanol(95/5), ammonia atmosphere). The solvent was removed under reducedpressure, and the residue was crystallized with oxalic acid from diethylether/ethanol. SF: C₁₆H₂₆N₄O₂ × C₂H₂O₄ (396.4)   mp: 118.6-119.7° C. CHNanalysis calculated: C 54.5 H 7.12 N 14.1 found: C 54.4 H 7.18 N 14.2

Example 134

[0988] 3-Nitro-2-(6-piperidinohexylamino)pyridine

[0989] 6-Aminohexanol (15 mmol), 15 mmol of 2-chloro-3-nitropyridine, 5ml of triethylamine and a catalytic amount of potassium iodide wererefluxed in 30 ml of ethanol for 12 hours. The solvent was evaporatedand the residue was purified by column chromatography on silica gel(eluent: methylene chloride/methanol (98/2), ammonia atmosphere). Thesolvent was removed under reduced pressure (Yield: 55%). The product (5mmol) was dissolved in tetrahydrofurane, stirred at 0° C. and 10 mmol ofthionyl chloride was added dropwise. After 1 hour at ambient temperaturethe mixture was warmed to 60° C. for 2 hours. The solvent and the excessof thionyl chloride were evaporated. The oily residue was crystallizedwith hydrochloric acid from diethyl ether/ethanol (Yield: 95%). Theproduct (5 mmol), 10 mmol of piperidine, 15 mmol of potassium carbonate,and a catalytic amount of potassium iodide were refluxed in 30 ml ofethanol for 12 hours. The solvent was evaporated and the residuepurified by column chromatography (eluent: methylene chloride/methanol(95/5), ammonia atmosphere). The solvent was removed under reducedpressure, and the residue was crystallized with oxalic acid from diethylether/ethanol SF: C₁₆H₂₆N₄O₂ × C₂H₂O₄ (396.4)   mp: 130.3-130.7° C. CHNanalysis calculated: C 54.5 H 7.12 N 14.1 found: C 54.3 H 7.14 N 13.9

Example 135

[0990] 2-(6-Piperidinohexylamino)pyrimidine

[0991] 6-Aminohexanol (15 mmol), 15 mmol of 2-chloropyrimidine, 5 ml oftriethylamine, and a catalytic amount of potassium iodide were refluxedin 30 ml of ethanol for 12 hours. The solvent was evaporated, and theresidue was purified by column chromatography on silica gel (eluent:methylene chloride/methanol (98/2), ammonia atmosphere). The solvent wasremoved under reduced pressure (Yield: 40%). The product (5 mmol) wasdissolved in tetrahydrofurane, stirred at 0° C. and 10 mmol of thionylchloride was added dropwise. After 1 hour at ambient temperature themixture was warmed to 60° C. for 2 hours. The solvent and the excess ofthionyl chloride were evaporated. The oily residue was crystallized withhydrochloric acid from diethyl ether/ethanol (Yield: 95%). The product(5 mmol), 10 mmol of piperidine, 15 mmol of potassium carbonate, and acatalytic amount of potassium iodide were refluxed in 30 ml of ethanolfor 12 hours. The solvent was evaporated and the residue purified bycolumn chromatography (eluent: methylene chloride/methanol (95/5),ammonia atmosphere). The solvent was removed under reduced pressure, andthe residue was crystallized with oxalic acid from diethylether/ethanol. SF: C₁₅H₂₆N₄ × C₂H₂O₄ (352.4)     mp: 150.3-150.9° C. CHNanalysis calculated: C 57.9 H 8.00 N 15.9 found: C 58.0 H 8.14 N 15.8

Example 136

[0992] N-(6-Phenylhexyl)piperidine

[0993] 6-Phenylhexanol (5 mmol) was stirred at 0° C., and thionylchloride (10 mmol) was added dropwise. After 1 hour at ambient temp. themixture was warmed to 60° C. for 2 hours. The excess of thionyl chloridewas evaporated. The oily residue was purified by column chromatographyon silica gel (eluent: methylene chloride) (Yield: 98%). The product wasdissolved in 50 ml of ethanol, and 10 mmol of K₂CO₃, 1 mmol of Kl, and10 mmol of piperidine were added. After refluxing for 6 hours thesolvent was evaporated under reduced pressure. The residue was suspendedin water and extracted with methylene chloride. The organic extractswere combined, dried with MgSO₄ and the residue purified by columnchromatography on silica gel (eluent: methylenechloride/methanol/aqueous ammonia (90/10/1)). The residue wascrystallized with oxalic acid from diethyl ether/methanol. SF: C₁₇H₂₇N ×C₂H₂O₄ (335.5)     mp: 152° C. CHN analysis calculated: C 68.0 H 8.71 N4.18 found: C 68.0 H 8.67 N 4.05

Example 137

[0994] α-(4-Acetylphenoxy)-α′-(4-methylpiperidino)p-xylol

[0995] α,α′-Dibromo-para-xylene (30 mmol), 4-hydroxyacetophenone (20mmol), and potassium carbonate (50 mmol) were refluxed in 50 ml ofacetone for 12 hours. The solvent was removed under reduced pressure andthe residue purified by column chromatography on silica gel (eluent:methylene chloride/petroleum ether/methanol (60/38/2)).

[0996] The product (2 mmol), 4-methylpiperidine (6 mmol), potassiumcarbonate (8 mmol), and catalytic amounts of potassium iodide wererefluxed in acetone for 12 hours. The solvent was evaporated. Theresidue was washed with water and extracted with ethyl acetate. Thesolvent was removed under reduced pressure. The product was crystallizedwith oxalic acid from diethyl ether/ethanol. SF: C₂₂H₂₇NO₂ × C₂H₂O₄ ×0.75 H₂O (440.7)     mp: 145° C. CHN analysis calculated: C 65.41 H 6.92N 3.18 found: C 65.12 H 6.69 N 3.17

Example 138

[0997] α-(4-Acetylphenoxy)-α′-(3,5-cis-dimethylpiperidino)p-xylol

[0998] Following the procedure described in example 137, the etherobtained (2 mmol), 3,5-dimethylpiperidine (mixture of cis and trans, 8mmol), potassium carbonate (8 mmol), and catalytic amounts of potassiumiodide were refluxed in acetone for 12 hours. After evaporating thesolvent the product was purified by column chromatography on silica geland thereby separated from the corresponding diastereomer (eluent:diethyl ether/petroleum ether/triethylamine (66/33/1)). The product wascrystallized with oxalic acid from diethyl ether/ethanol. SF: C₂₃H₂₉NO₂× C₂H₂O₄ × 0.5 H₂O (450.2)     mp: 148° C. CHN analysis calculated: C66.69 H 7.11 N 3.11 found: C 66.95 H 7.30 N 3.20

Example 139

[0999] α-(4-Acetylphenoxy)-α′-(3,5-trans-dimethylpiperidino)p-xylol

[1000] Following the procedure described in example 137, the etherobtained (2 mmol), 3,5-dimethylpiperidine (mixture of cis and trans, 8mmol), potassium carbonate (8 mmol), and catalytic amounts of potassiumiodide were refluxed in acetone for 12 hours. After evaporating thesolvent the product was purified by column chromatography on silica geland thereby separated from the corresponding diastereomer (eluent:diethyl ether/petroleum ether/triethylamine (66/33/1)). The product wascrystallized with oxalic acid from diethyl ether/ethanol. SF: C₂₃H₂₉NO₂× C₂H₂O₄ × 0.5 H₂O (450.2)     mp: 141° C. CHN analysis calculated: C66.69 H 7.11 N 3.11 found: C 66.94 H 7.17 N 3.19

Example 140

[1001] α-(4-Acetylphenoxy)-α′-(2-methylpyrrolidino)p-xylol

[1002] Following the procedure described in example 137, the etherobtained (2 mmol), 2-methylpyrrolidine (6 mmol), potassium carbonate (8mmol) and catalytic amounts of potassium iodide were refluxed -inacetone for 12 hours. The solvent was evaporated. The residue was washedwith water and extracted with ethyl acetate. The solvent was removedunder reduced pressure. The product was crystallized with hydrochloricacid from diethyl ether/ethanol. Recrystallization resulted in the pureproduct. SF: C₂₁H₂₅NO₂ × HCl × 0.25 H₂O (361.1)     mp: 324° C. CHNanalysis calculated: C 69.26 H 7.00 N 3.85 found: C 69.52 H 7.12 N 3.85

Example 141

[1003] α-(4-Cyclopropylcarbonylphenoxy)-α′-piperidino-p-xylol

[1004] A solution containing 1,4-benzenedimethanol (30 mmol), sodiumhydride (25 mmol), catalytic amounts of tetrabutylammonium iodide, and15-crown-5 (0.5 mmol) in tetrahyrofuran was stirred for 10 minutes.Cyclopropyl-4-fluorophenylketone (20 mmol) was added dropwise, and thesolution was refluxed for 24 hours. The solvent was removed underreduced pressure. The residue was purified by column chromatography onsilica gel (eluent: methylene chloride/methanol (98/2)).

[1005] At 0° C. the product (4 mmol) was added to thionyl chloride (8mmol). The temperature was raised to 70° C. for three hours. Excessthionyl chloride was evaporated and the residue purified by columnchromatography on silica gel (eluent: methylene chloride/methanol(95/5)). The product (2 mmol), piperidine (4 mmol), catalytic amounts ofpotassium iodide, and potassium carbonate (6 mmol) dissolved in acetonewere refluxed for 12 hours. The solvent was evaporated. The crudeproduct was washed with water and extracted with ethyl acetate. Theorganic layer was removed under reduced pressure. The residue wascrystallized with oxalic acid from diethyl ether/ethanol. SF: C₂₃H₂₇NO₂× C₂H₂O₄ (439.2)     mp: 194° C. CHN analysis calculated: C 68.33 H 6.61N 3.19 found: C 68.38 H 6.78 N 3.29

Example 142

[1006] α-(4-Cyclopropylcarbonylphenoxy)-α′-(4-methylpiperidino)p-xylol

[1007] Following the procedure described in example 141, the chlorideobtained (2 mmol), 4-methylpiperidine (4 mmol), potassium carbonate (6mmol), and catalytic amounts of potassium iodide were refluxed inacetone for 12 hours. The solvent was evaporated. The crude product waswashed with water and extracted with ethyl acetate. The organic layerwas removed under reduced pressure, and the residue was crystallizedwith oxalic acid from diethyl ether/ethanol. SF: C₂₄H₂₉NO₂ × C₂H₂O₄ ×0.75 H₂O (466.7)     mp: 169-170° C. CHN analysis calculated: C 66.91 H6.96 N 2.99 found: C 66.85 H 6.83 N 2.96

Example 143

[1008] α-(4-Cyclopropylcarbonylphenoxy)-α′-pyrrolidino-p-xylol

[1009] Following the procedure described in example 141, the chlorideobtained (2 mmol), pyrrolidine (4 mmol), catalytic amounts of potassiumiodide, and potassium carbonate (6 mmol) were refluxed in acetone for 12hours. The solvent was evaporated. The crude product was washed withwater and extracted with ethyl acetate. The organic layer was removedunder reduced pressure, and the residue was crystallized with oxalicacid from diethyl ether/ethanol. SF: C₂₂H₂₅NO₂ × C₂H₂O₄ × 0.5 H₂O(434.2)     mp: 179° C. CHN analysis calculated: C 66.38 H 6.45 N 3.22found: C 66.61 H 6.45 N 3.22

Example 144

[1010] 3-Phenylpropyl 3-(4-methylpiperidino)propyl ether

[1011] 3-Phenylpropylmesilate (18 mmol), catalytic amounts oftetrabutylammonium iodide, and 15-crown-5 (0.5 mmol) were added underargon atmosphere to a solution of 1,3-propanediol (25 mmol) and sodiumhydride (25 mmol) in tetrahydrofuran which had been stirred over night.The mixture was refluxed for 24 hours. The solvent was evaporated andthe oily residue purified by column chromatography (eluent: methylenechloride/methanol (95/5)). At 0° C. the product (8 mmol) was added tothionyl chloride (16 mmol). The temperature was raised to 70° C. forthree hours. Excess thionyl chloride was evaporated. The residue waspurified by column chromatography on silica gel (eluent: methylenechloride), and the solvent was evaporated under reduced pressure. Thechloride obtained (5 mmol), 4-methylpiperidine (10 mmol), potassiumcarbonate (15 mmol), and catalytic amounts of potassium iodide weredissolved in acetone and refluxed for 12 hours. After evaporating thesolvent the product was purified by column chromatography on silica gel(eluent: diethyl ether/petroleum ether/triethylamine (66/33/1)) andcrystallized with oxalic acid from diethyl ether/ethanol. SF: C₁₈H₂₉NO ×C₂H₂O₄ (365.4)     mp: 119-120° C. CHN analysis calculated: C 65.73 H8.55 N 3.83 found: C 65.44 H 8.83 N 3.79

Example 145

[1012] 3-Phenylpropyl 3-(3,5-cis-dimethylpiperidino)propyl ether

[1013] Following the procedure described in example 144 the chlorideobtained (5 mmol), 3,5-dimethylpiperidine (mixture of cis and trans, 10mmol), potassium carbonate (15 mmol), and catalytic amounts of potassiumiodide were dissolved in acetone and refluxed for 12 hours. Afterevaporating the solvent the product was purified by columnchromatography on silica gel and thereby separated from thecorresponding diastereomer (eluent: diethyl ether/petroleumether/triethylamine (66/33/1)). The product was crystallized with oxalicacid from diethyl ether/ethanol. SF: C₁₉H₃₁NO × C₂H₂O₄ (379.5)   mp:107-108° C. CHN analysis calculated: C 66.46 H 8.76 N 3.69 found: C66.42 H 8.54 N 3.67

Example 146

[1014] 3-Phenylpropyl 3-(3,5-trans-dimethylpiperidino)propyl ether

[1015] Following the procedure described in example 143 the chlorideobtained (5 mmol), 3,5-dimethylpiperidine (mixture of cis and trans, 10mmol), potassium carbonate (15 mmol), and catalytic amounts of potassiumiodide were dissolved in acetone and refluxed for 12 hours. Afterevaporating the solvent the product was purified by columnchromatography on silica gel and thereby separated from thecorresponding diastereomer (eluent: diethyl ether/petroleumether/triethylamine (66/33/1)). The product was crystallized with oxalicacid from diethyl ether/ethanol. SF: C₁₉H₃₁NO × C₂H₂O₄ (379.5)   mp:123.5° C. CHN analysis calculated: C 66.46 H 8.76 N 3.69 found: C 66.35H 8.72 N 3.75

Example 147

[1016] 3-Phenylpropyl 3-(3-methylpiperidino)propyl ether

[1017] Following the procedure described in example 143 the chlorideobtained (5 mmol), 3-methylpiperidine (10 mmol), potassium carbonate (15mmol), and catalytic amounts of potassium iodide were dissolved inacetone and refluxed for 12 hours. After evaporating the solvent theproduct was purified by column chromatography on silica gel (eluent:diethyl ether/petroleum ether/triethylamine (66/33/1)). The product wascrystallized with oxalic acid from diethyl ether/ethanol. SF: C₁₈H₂₉NO ×C₂H₂O₄ (365.4)   mp: 123° C. CHN analysis calculated: C 65.73 H 8.55 N3.83 found: C 65.39 H 8.72 N 3.79

Example 148

[1018] 3-Phenylpropyl 3-pyrrolidinopropyl ether

[1019] Following the procedure described in example 143 the chlorideobtained (5 mmol), pyrrolidine (10 mmol), potassium carbonate (15 mmol),and catalytic amounts of potassium iodide were dissolved in acetone andrefluxed for 12 hours. After evaporating the solvent the product waspurified by column chromatography on silica gel (eluent: diethylether/petroleum ether/triethylamine (66/3311)). The product wascrystallized with oxalic acid from diethyl ether/ethanol. SF: C₁₅H₂₅NO ×C₂H₂O₄ (337.4)   mp: 105.5° C. CHN analysis calculated: C 64.07 H 8.07 N4.15 found: C 63.85 H 7.84 N 4.13

Example 149

[1020] 3-(4-Chlorophenyl)propyl 3-(4-methylpiperidino)propyl ether

[1021] 3-(4-Chlorophenyl)propylmesilate (18 mmol), catalytic amounts oftetrabutyl-ammonium iodide, and 15-crown-5 (0.5 mmol) were added underargon atmosphere to a solution of 1,3-propanediol (25 mmol) and sodiumhydride (25 mmol) in tetrahydrofuran which had been stirred over night.The mixture was refluxed for 24 hours. The solvent was evaporated andthe oily residue purified by column chromatography (eluent: methylenechloride/methanol (95/5)). At 0° C. the product (8 mmol) was added tothionyl chloride (16 mmol). The temperature was raised to 70° C. forthree hours. Excess thionyl chloride was evaporated. The residue waspurified by column chromatography on silica gel (eluent: methylenechloride) and the solvent was evaporated under reduced pressure. Thechloride obtained (5 mmol), 4-methylpiperidine (10 mmol), potassiumcarbonate (15 mmol), and catalytic amounts of potassium iodide weredissolved in acetone and refluxed for 12 hours. After evaporating thesolvent the product was purified by column chromatography on silica gel(eluent: diethyl ether/petroleum ether/triethylamine (66/33/1)) andcrystallized with oxalic acid from diethyl ether/ethanol. SF: C₁₈H₂₈NOCl× C₂H₂O₄ (399.9)   mp: 116° C. CHN analysis calculated: C 60.08 H 7.56 N3.50 found: C 59.78 H 7.33 N 3.49

Example 150

[1022] 3-(4-Chlorophenyl)propyl 3-(3,5-cis-dimethylpiperidino)propylether

[1023] Following the procedure described in example 149 the chlorideobtained (5 mmol), 3,5-dimethylpiperidine (mixture of cis and trans, 10mmol), potassium carbonate (15 mmol), and catalytic amounts of potassiumiodide were dissolved in acetone and refluxed for 12 hours. Afterevaporating the solvent the product was purified by columnchromatography on silica gel and thereby separated from thecorresponding diastereomer (eluent: diethyl ether/petroleumether/triethylamine (66/33/1)). The product was crystallized with oxalicacid from diethyl ether/ethanol. SF: C₁₉H₃₀NOCl × C₂H₂O₄ × 0.25 H₂O(418.5)   mp: 117.5° C. CHN analysis calculated: C 66.46 H 8.76 N 3.69found: C 66.42 H 8.54 N 3.67

Example 151

[1024] 3-(4-Chlorophenyl)propyl 3-(3,5-trans-dimethylpiperidino)propylether

[1025] Following the procedure described in example 149 the chlorideobtained (5 mmol), 3,5-dimethylpiperidine (mixture of cis and trans, 10mmol), potassium carbonate (15 mmol), and catalytic amounts of potassiumiodide were dissolved in acetone and refluxed for 12 hours. Afterevaporating the solvent the product was purified by columnchromatography on silica gel and thereby separated from thecorresponding diastereomer (eluent: diethyl ether/petroleumether/triethylamine (66/33/1)). The product was crystallized with oxalicacid from diethyl ether/ethanol. SF: C₁₉H₃₀NOCl × C₂H₂O₄ (413.4)   mp:150° C. CHN analysis calculated: C 60.93 H 7.79 N 3.38 found: C 60.95 H7.39 N 3.34

Example 152

[1026] 4-(6-Piperidinohexylamino)quinoline

[1027] 6-Aminohexanol (15 mmol), 4-chloroquinoline (15 mmol), 5 ml oftriethylamine and catalytic amounts of potassium iodide were refluxed inethanol for 12 hours. The solvent was evaporated and the residue waspurified by flash chromatography on silica gel (eluent: methylenechloride/methanol (98/2), ammonia atmosphere). The solvent was removedunder reduced pressure. At 0° C. the product (5 mmol) was added tothionyl chloride (10 mmol). The temperature was raised to 70° C. forthree hours. Excess thionyl chloride was evaporated. The residue wasrecrystallized from diethyl ether/ethanol. The product (5 mmol),piperidine (10 mmol), potassium carbonate (15 mmol), and catalyticamounts of potassium iodide were refluxed in acetone for 12 hours. Thesolvent was evaporated and the residue purified by flash chromatography(eluent: ethyl acetate/methanol/triethylamine (95/5/2)). The solvent wasremoved under reduced pressure. The residue was crystallized with oxalicacid from diethyl ether/ethanol. SF: C₂₀H₂₉N₃ × 2 C₂H₂O₄ × 0.5 H₂0(500.6)   mp: 167.3-168.1° C. CHN analysis calculated: C 57.6 H 6.85 N8.39 found: C 57.7 H 6.55 N 8.42

Example 153

[1028] 2-Methyl 4-(3-piperidinopropylamino)quinoline

[1029] Synthesis and purification were performed according to theprocedure stated in example 152 using reagents 3-aminopropanol (15mmol), 4-chloro-2-methylquinoline (15 mmol), 5 ml of triethylamine, andcatalytic amounts of potassium iodide in the first step. The finalproduct was purified by flash chromatography (eluent: ethylacetate/triethylamine (95/5)). The solvent was removed under reducedpressure. The residue was crystallized with oxalic acid from diethylether/ethanol. SF: C₁₈H₂₅N₃ × 2 C₂H₂O₄ (463.5)   mp: 185.5-186.3° C. CHNanalysis calculated: C 57.0 H 6.31 N 9.07 found: C 56.9 H 6.19 N 8.98

Example 154

[1030] 2-Methyl 4-(6-piperidinohexylamino)quinoline

[1031] Synthesis and purification were performed according to theprocedure stated in example 152 using reagents 6-aminohexanol (15 mmol),4-chloro-2-methylquinoline (15 mmol), 5 ml of triethylamine, andcatalytic amounts of potassium iodide in the first step. The finalproduct was purified by column chromatography (eluent: ethylacetate/triethylamine (95/5)). The solvent was removed under reducedpressure. The residue was crystallized with oxalic acid from diethylether/ethanol. SF: C₂₁H₃₁N₃ × 2 C₂H₂O₄ × 0.75 H₂₀ (519.1)   mp:193.6-194.0° C. CHN analysis calculated: C 57.9 H 7.09 N 8.10 found: C57.8 H 7.08 N 7.85

Example 155

[1032] 7-Chloro-4-(3-piperidinopropylamino)quinoline

[1033] Synthesis and purification were performed according to theprocedure stated in example 152 using reagents 3-aminohexanol (15 mmol),4,7-dichloroquinoline (15 mmol), 5 ml of triethylamine, and catalyticamounts of potassium iodide in the first step. The final product waspurified by column chromatography (eluent: ethyl acetate/triethylamine(90/10)). The solvent was removed under reduced pressure. The residuewas crystallized with oxalic acid from diethyl ether/ethanol SF:C₁₇H₂₂ClN₃ × 2 C₂H₂O₄ (483.9)   mp: 202.9-204.0° C. CHN analysiscalculated: C 52.1 H 5.42 N 8.68 found: C 51.9 H 5.25 N 8.65

Example 156

[1034] 7-Chloro-4-(4-piperidinobutylamino)quinoline

[1035] Synthesis and purification were performed according to theprocedure stated in example 152 using reagents 3-aminobutanol (15 mmol),4,7-dichloroquinoline (15 mmol), 5 ml of triethylamine, and catalyticamounts of potassium iodide in the first step. The final product waspurified by column chromatography (eluent: ethyl acetate/triethylamine(90/10)).The solvent was removed under reduced pressure. The residue wascrystallized with oxalic acid from diethyl ether/ethanol. SF: C₁₈H₂₄ClN₃× 2 C₂H₂O₄ × 0.5 H₂O (506.9)  mp: 162.6-163.5° C. CHN analysiscalculated: C 52.1 H 5.76 N 8.28 found: C 52.2 H 5.64 N 8.15

Example 157

[1036] 7-Chloro-4-(8-piperidinooctylamino)quinoline

[1037] 1,8-Dibromooctane (30 mmol), potassium phthalimide (15 mmol), andcatalytic amounts of potassium iodide were refluxed in acetone for 3days. The solvent was evaporated, and the residue was purified by flashchromatography on silica gel (eluent: methylene chloride/petroleum ether(60/40)). The solvent was removed under reduced pressure. The product(12.5 mmol), piperidine (50 mmol), and catalytic amounts of potassiumiodide were refluxed in acetone for 12 hours. Solvent and piperidinewere evaporated. The residue was treated with hydrochloric acid (2N),with potassium carbonate solution and was then extracted with methylenechloride. The solvent was removed under reduced pressure, and theresidue was refluxed in hydrochloric acid (6N) for 12 hours. Thesolution was neutralized with potassium carbonate solution and extractedwith methylene chloride. The organic layer was evaporated and theproduct was purified by flash chromatography on silica gel (eluent:methylene chloride/triethylamine/ methanol (90/10/2)). The product (5mmol), 4,7-dichloroquinoline (5 mmol), and catalytic amounts ofpotassium iodide were melted with 10 g of phenole for 12 hours. Theresidue was purified by flash chromatography (eluent: ethylacetate/triethylamine (95/5)). The solvent was removed under reducedpressure. The residue was crystallized with oxalic acid from diethylether/ethanol. SF: C₂₂H₃₂ClN₃ × 2 C₂H₂O₄ (554.0)   mp: 150.7-150.9° C.CHN analysis calculated: C 56.4 H 6.55 N 7.58 found: C 56.2 H 6.48 N7.42

Example 158

[1038] 7-Chloro-4-(10-piperidinodecylamino)quinoline

[1039] Synthesis and purification were performed according to theprocedure described in example 157 using reagents 1,10-dibromodecane (30mmol), potassium phthalimide (15 mmol), and catalytic amounts ofpotassium iodide in the first step. The final product was purified bycolumn chromatography (eluent: ethyl acetate/triethylamine 95/5). Thesolvent was removed under reduced pressure. The residue was crystallizedwith oxalic acid from diethyl ether/ethanol. SF: C₂₄H₃₆ClN₃ × 2 C₂H₂O₄(582.1)   mp: 151.2-151.5° C. CHN analysis calculated: C 57.8 H 6.93 N7.22 found: C 57.4 H 6.81 N 7.07

Example 159

[1040] 7-Chloro-4-(12-piperidinododecylamino)quinoline

[1041] Synthesis and purification were performed according to theprocedure described in example 157 using regents 1,12-dibromododecane(30 mmol), potassium phthalimide (15 mmol), and catalytic amounts ofpotassium iodide in the first step. The residue was purified by flashchromatography (eluent: ethyl acetate/triethylamine (95/5)). The solventwas removed under reduced pressure. The residue was crystallized withoxalic acid from diethyl ether/ethanol. SF: C₂₆H₄₀ClN₃ × 2 C₂H₂O₄(610.2)   mp: 141.6-142.9° C. CHN analysis calculated: C 59.1 H 7.27 N6.89 found: C 58.7 H 7.30 N 6.78

Example 160

[1042] 7-Chloro-4-(4-(3-piperidinopropoxy)phenylamino)quinoline

[1043] 4-Hydroxyaniline (11 mmol), 4,7-dichloroquinoline (10 mmol ), 1ml of 2N hydrochloric acid, and catalytic amounts of potassium iodidewere refluxed in acetone for 12 hours. The product was filtered. Theproduct (5 mmol), 3-piperidinopropylchloride hydrochloride (5 mmol),potassium carbonate (15 mmol), and catalytic amounts of potassium iodidewere refluxed in acetone for 22 hours. The product was filtered andpurified by flash chromatography (eluent: methylene chloride/petroleumether/triethylamine (95/25/5)). The solvent was removed under reducedpressure. The residue was crystallized with oxalic acid from diethylether/ethanol. SF: C₂₃H₂₆ClN₃₀ × 2 C₂H₂O₄ × 0.25 H₂O (580.5) mp:189.8-190.3° C. CHN analysis calculated: C 55.9 H 5.29 N 7.23 found: C55.7 H 5.43 N 7.14

Example 161

[1044] 7-Chloro-4-(2-(4-(3-piperidinopropoxy)phenyl)ethylamino)quinoline

[1045] Tyramine (10 mmol), 4,7-dichloroquinoline, and catalytic amountsof potassium iodide were melted in 10 g of phenol at 150° C. for 12hours. The residue was crystallized with hydrochloric acid from ethylacetate/water. The product (5 mmol), 3-piperidinopropylchloridehydrochloride (5 mmol), potassium carbonate (15 mmol), and catalyticamounts of potassium iodide were refluxed in N,N-dimethylformamide for22 hours. The solvent was evaporated and the residue purified by flashchromatography (eluent: ethyl acetate/petroleum ether/triethylamine(95/50/5)). The solvent was removed under reduced pressure. The residuewas crystallized with oxalic acid from diethyl ether/ethanol. SF:C₂₅H₃₀ClN₃₀ × 2 C₂H₂O₄ × H₂O (622.1)   mp: 149.8-150.2° C. CHN analysiscalculated: C 56.0 H 5.83 N 6.75 found: C 55.7 H 5.77 N 6.46

Example 162

[1046] 4-(6-Piperidinohexanoyl)phenyl 3-piperidinopropyl ether

[1047] 3-Phenoxypropylbromide (10 mmol), piperidine (20 mmol), andcatalytic amounts of potassium iodide were refluxed in acetone for 12hours. The solvent was evaporated. The residue was treated with ethylacetate. The solvent was removed under reduced pressure, and the productwas crystallized with hydrochloric acid from isopropanol/diethyl ether.The product (5 mmol) was added to a solution of 6-bromohexanoylchloride(7.5 mmol) and aluminiumtrichloride (22.5 mmol) in 10 ml of nitrobenzol.The mixture was stirred at room temperature for 3 days. Ethyl acetatewas added, and the mixture was extracted with hydrochloric acid (6N).The solution was neutralized with potassium carbonate solution andextracted with methylene chloride. The solvent was removed under reducedpressure. The product (2.5 mmol), piperidine (5 mmol), potassiumcarbonate (7.5 mmol), and catalytic amounts of potassium iodide wererefluxed in acetone for 12 hours. The solvent was evaporated, and theresidue was purified by flash chromatography (eluent: methylenechloride/petroleum ether/methanol (96/3/3)). The solvent was removedunder reduced pressure. The residue was crystallized with oxalic acidfrom diethyl ether/ethanol. SF: C₂₅H₄₀N₂O₂ × 2 C₂H₂O₄ (580.7)   mp:149.1-149.5° C. CHN analysis calculated: C 60.0 H 7.64 N 4.82 found: C59.9 H 7.59 N 4.81

Example 163

[1048] 5-Nitro-2-(5-piperidinopentylamino)pyridine

[1049] Synthesis and purification were performed according to theprocedure stated in example 152 using reagents 5-aminopentanol (15mmol), 2-chloro-5-nitropyridine (15 mmol), 5 ml of triethylamine, andcatalytic amounts of potassium iodide in the first step. The finalproduct was purified by column chromatography (eluent: ethylacetate/triethylamine (90/10)). The solvent was removed under reducedpressure. The residue was crystallized with oxalic acid from diethylether/ethanol. SF: C₁₅H₂₄N₄O₂ × C₂H₂O₄ (382.4)   mp: 95.7-96.0° C. CHNanalysis calculated: C 53.4 H 6.85 N 14.65 found: C 53.6 H 7.00 N 14.55

Example 164

[1050] 3-Nitro-2-(6-piperidinopentylamino)pyridine

[1051] Synthesis and purification were performed according to theprocedure stated in example 152 using reagents 5-aminopentanol (15mmol), 2-chloro-3-nitropyridine (15 mmol), 5 ml of triethylamine, andcatalytic amounts of potassium iodide in the first step, The finalproduct was purified by column chromatography (eluent: ethylacetate/triethylamine (95/5), ammonia atmosphere). The solvent wasremoved under reduced pressure. The residue was crystallized with oxalicacid from diethyl ether/ethanol. SF: C₁₅H₂₄N₄O₂ × C₂H₂O₄ × 0.25 H₂O(386.9)  mp: 148.5-149.2° C. CHN analysis calculated: C 52.8 H 6.90 N14.48 found: C 52.8 H 6.80 N 14.51

Example 165

[1052] 5-Amino-2-(6-piperidinopentylamino)pyridine

[1053] Synthesis and purification were performed according to theprocedure stated in example 152 using reagents 5-aminopentanol (15mmol), 2-chloro-5-nitropyridine (15 mmol), 5 ml of triethylamine, andcatalytic amounts of potassium iodide in the first step. The product waspurified by column chromatography on silica gel (eluent: methylenechloride/methanol (95/5), ammonia atmosphere) and dissolved in 20 ml oftetrahydrofuran. 100 mg of palladium/active charcoal (10%) was added,and the mixture was hydrogenated at 1 bar H2 for 12 hours. The solventwas removed under reduced pressure, and the residue was crystallizedwith oxalic acid from diethyl ether/ethanol. SF: C₁₅H₂₆N₄ × 2 C₂H₂O₄(442.5)   mp: 85.7-87.3° C. CHN analysis calculated: C 51.6 H 6.83 N12.66 found: C 51.4 H 6.81 N 12.83

Example 166

[1054] 2-(6-Piperidinohexylamino)quinoline

[1055] Synthesis and purification were performed according to theprocedure stated in example 152 using reagents 6-aminohexanol (15 mmol),2-chloroquinolin (15 mmol), 5 ml of triethylamine, and catalytic amountsof potassium iodide in the first step. The final product was purified byflash chromatography (eluent: ethyl acetate/triethylamine (95/5)). Thesolvent was removed under reduced pressure, and the residue wascrystallized with oxalic acid from diethyl ether/ethanol. SF: C₂₀H₂₉N₃ ×2 C₂H₂O₄ × 0.75 H₂O (505.1)   mp: 90.7-91.5° C. CHN analysis calculated:C 57.1 H 6.88 N 8.32 found: C 57.1 H 6.54 N 8.17

Example 167

[1056] N-(4-Chlorobenzyl)-N′-cyclohexyl-3-piperidinopropyl isothiourea

[1057] Cyclohexylamine (10 mmol) was added dropwise to4-chlorobenzylisothiocyanate (10 mmol) dissolved in 20 ml of dry ether.The solution was stirred for 2 hours at room temperature. Theprecipitated product was filtered off and crystallized from ethylacetate. 3-Piperidinopropyl chloride hydrochloride (3 mmol), the product(3 mmol), and ca-talytic amounts of potassium iodide were refluxed inethanol for 6 days. Sub-sequently, ethanol was evaporated, and theresidue was purified by column chromato-graphy (eluent: methylenechloride/methanol (95/5)). After evaporation of the solvent the productwas crystallized with hydrochloric acid from diethyl ether/ethanol. SF:C₂₂H₃₄ClN₃S × 2 HCl × H₂O (499.0)   mp: 103.0-107.0° C. CHN analysiscalculated: C 53.0 H 7.68 N 8.42 found: C 52.6 H 7.88 N 8.24

Example 168

[1058] 2-(6-Piperidinohexylamino)benzothiazole

[1059] Synthesis and purification were performed according to theprocedure stated in example 152 using reagents 6-aminohexanol (15 mmol),2-chlorobenzothiazole (15 mmol), 5 ml of triethylamine, and catalyticamounts of potassium iodide in the first step. The final product waspurified by flash chromatography (eluent: methylene chloride/methanol(95/5), ammonia atmosphere). The solvent was removed under reducedpressure, and the residue was crystallized with oxalic acid from diethylether/ethanol. SF: C₁₈H₂₇N₃S × 1.9 C₂H₂O₄ (488.6)   mp: 98.5-101.8° C.CHN analysis calculated: C 53.6 H 6.35 N 8.60 found: C 54.0 H 6.43 N8.33

Example 169

[1060] 10-Piperidinodecylamine

[1061] The synthesis was performed according to the procedure describedin example 157 using reagents 1,10-dibromodecane (30 mmol), potassiumphthalimide (15 mmol), and catalytic amounts of potassium iodide in thefirst step. The product (12.5 mmol), piperidine (50 mmol) and catalyticamounts of potassium iodide were refluxed in acetone for 12 hours.Solvent and piperidine were evaporated. The residue was treated withhydrochloric acid (2N), with potassium carbonate solution and thenextracted with methylene chloride. The solvent was removed under reducedpressure, and the residue was refluxed in hydrochloric acid (6N) for 12hours. The solution was neutralized with potassium carbonate solutionand extracted with methylene chloride. The organic layer was evaporated,and the final product purified by flash chromatography (eluent:methylene chloride/triethylamine/methanol (90/10/2)). The solvent wasremoved under reduced pressure. The residue was crystallized with oxalicacid from diethyl ether/ethanol. SF: C₁₅H₃₂N₂ × 2 C₂H₂O₄ × 0.75 H₂O(434.0)  mp: 116.1-117.2° C. CHN analysis calculated: C 52.6 H 8.71 N6.45 found: C 52.5 H 8.70 N 6.35

Example 170

[1062] 3-Phenylpropyl 3-(N,N-diethylamino)propyl ether

[1063] Following the procedure described in example 144 the chlorideobtained (5 mmol), diethylamine (10 mmol), potassium carbonate (15mmol), and catalytic amounts of potassium iodide were dissolved inacetone and refluxed for 12 hours. After evaporating the solvent theproduct was purified by column chromatography on silica gel (eluent:diethyl ether/petroleum ether/triethylamine (66/33/1)). The product wascrystallized with oxalic acid from diethyl ether/ethanol. SF: C₁₆H₂₇NO ×C₂H₂O₄ (340.3)   mp: 80° C. CHN analysis calculated: C 63.69 H 8.61 N4.13 found: C 63.52 H 8.40 N 4.06

[1064] Pharmacological Study

[1065] Interaction of compounds with the H₃ receptor are evidenced invitro by the measurement of the release of neosynthesized tritiatedhistamine from rat cerebral cortex synaptosomes preincubated withtritiated histidine (Garbarg et al., J. Pharmacol. Exp. Ther., 1992, 263: 304-310). The H₃ potency of agonists is measured by the inhibition oftritiated histamine release and that of antagonists by the progressivereversal of release inhibition by the selective H₃ agonist(R)α-methylhistamine (Arrang et al., Nature, 1987, 327: 117-123).

[1066] Interaction of compounds with the H₃ receptor are evidenced invitro on guinea-pig ileum by the procedure described by Ligneau et al.,J. Pharmacol. Exp. Ther. 271, 452-459 (1994).

[1067] Briefly, longitudinal muscle strips from guinea-pig smallintestine were dissected out and incubated in a gassed O₂/CO₂ (95%/5%)modified Krebs-Ringer's bicarbonate medium at +37° C. in presence of 1μM mepyramine to block the H₁ receptor. After equilibration, contractileactivity under stimulation (rectangular pulses of 15 V, 0.5 msec, 0.1Hz) was recorded.

[1068] Concentration-response curves of the effect of(R)α-Methylhistamine alone or together with the antagonist wereestablished.

[1069] The effects of agonists and antagonists were estimated in vivo bythe measurement of the tele-methylhistamine level variations in thebrain of mice (Garbarg et al., J. Neurochem., 1989, 53: 1724-1730). Atvarious time after p.o. administration of the compounds, the effect ofagonists and antagonists are evidenced by the decrease and increaserespectively in telemethylhistamine level induced.

[1070] The changes are compared to those induced by reference compoundsgiven in high dosage and this allows the calculation of the ED50 valuefor each compound which correspond to the dose responsible for an halfmaximal effect.

[1071] The results are listed here-below or reported in the followingtables II and III:

[1072] example 59: 1-[3-(4-cyanophenoxy)propyl]piperidine, ED₅₀=0.02mg/kg

[1073] example 74: 1-[3-(4-buyrylphenoxy)propyl]piperidine, ED₅₀=0.21mg/kg

[1074] example 76:1-[3-(4-cyclopropanecarbonylphenoxy)propyl]piperidine, ED₅₀=0.18 mg/kg

[1075] example 88: 1-[3-(4-propionylphenoxy)propyl]-3-methylpiperidine,ED₅₀=0.14 mg/kg

[1076] example 101: 1-[3-(4-cyclopropane carbonyl phenoxy)propyl]-trans-3,5 dimethylpiperidine, ED₅₀=0.17 mg/kg TABLE II R³ ED₅₀Ex No. X n R¹R² (n₃ = 1) Ki (nM) (mg/kg/p.o.) 18 O 5 —(CH₂)₄— p-NO₂ 39 ±11 1.1 43 O 3 Et, Et p-CN 95 ± 28 0.50 46 O 3 Et, Et p-CH₃CO 20 ± 7 0.44 50 O 5 —(CH₂)₄— p-CH₃CH(OH) 28 ± 7  1.0 56 O 4 Et, Et p-CN 62 ± 151.1 59 O 3 —(CH₂)₅— p-CN 11 ± 2  0.20 60 O 3 —(CH₂)₆— p-CN 8.7 ± 2.10.64 63 O 3 Et, Et p-CH₃CH(OH) 60 ± 18 0.45 64 O 3 Et, Et p-CH₃C═N(OH)2.7 ± 0.9 0.8 66 O 3 —(3-Me)—(CH₂)₅— p-CH₃CO 3.7 ± 0.5 0.3 68 O 3—(4-Me)—(CH₂)₅— p-CH₃CO 4.6 ± 2.0 0.5 69 O 3 —(CH₂)₅— p-C₂H₅CO 4.7 ± 0.80.6

[1077] TABLE III Example H₃-receptor antagonist activity No. pA₂(guinea-pig ileum) 120 6.3 124 6.4 130 7.2 131 6.6 136 6.5

[1078] All the above compounds were find to be H₃-antagonists.

[1079] Comparative data concerning the activity of imidazole derivativesand of the non-imidazole analogues according to the invention, arereported below in Table IV: TABLE IV Non-imidazole analogue Imidazolederivative according to the invention

1. A compound of formula (IIa)

wherein: R¹ and R² may be identical or different and represent eachindependently a saturated nitrogen-containing ring

with m ranging from 2 to 8, or R^(a-b) being independently a hydrogenatom or a lower alkyl, and (i′) the chain A^(II) selected from anunbranched alkyl group —(CH₂)_(nII)— where n_(II) is 3; (ii′) the groupX″ is —O—; (iii′) the chain B^(II) is an unbranched alkyl comprising 3carbon atoms; and (iv′) the group Y^(II) represents a phenyl group,unsubstituted or mono- or polysubstituted with one or more identical ordifferent substituents selected from halogen atoms, OCF₃, CHO, CF₃,SO₂N(alkyl)₂ such as SO₂N(CH₃)₂, NO₂, S(aryl), SCH₂(phenyl), anunbranched or branched alkene, an unbranched or branched alkyneoptionally substituted with a trialkylsilyl radical, —O(alkyl),—O(aryl), —CH₂CN, a ketone, an aldehyde, a sulphone, an acetal, analcohol, a lower alkyl, —CH═CH—CHO, —C(alkyl)=N—OH, —C(alkyl)=N—O(alkyl)and other keto derivatives, —CH=NOH, —CH═NO(alkyl), and other aldehydederivatives, —C(alkyl)=NH—NH—CONH₂, an O-phenyl or —OCH₂(phenyl) group,—C(cycloalkyl)=NOH, —C(cycloalkyl)=N—O(alkyl); or its pharmaceuticallyacceptable salts, hydrates, or hydrated salts, or the polymorphiccrystalline structures of these compounds or their optical isomers,racemates, diastereoisomers or enantiomers.
 2. The compound according toclaim 1, wherein —NR¹R² is a saturated nitrogen-containing ring:

and wherein R^(a) and m are defined in claim
 1. 3. The compoundaccording to claim 2, wherein m is 4 or
 5. 4. The compound according toclaim 3, wherein —NR¹R² is selected from the group consisting ofpiperidyl and pyrrolidinyl.
 5. The compound according to claim 2,wherein R^(a) is a hydrogen atom.
 6. The compound according to claim 2,wherein the nitrogen-containing ring i) is mono- or di-substituted. 7.The compound according to claim 6, wherein the nitrogen-containing ringi) is mono-substituted with an alkyl group.
 8. The compound according toclaim 6, wherein the nitrogen-containing ring is mono-substituted with amethyl group.
 9. The compound according to claim 6, wherein thesubstituent(s) is(are) in beta-position with respect to the nitrogenatom.
 10. The compound according to claim 1, wherein Y^(II) represents aphenyl group at least mono-substituted with a keto-substituent which mayinclude a linear or branched chain aliphatic ketone comprising from 1 to8 carbon atoms and optionally bearing a hydroxyl group, acycloalkylketone, an arylalkylketone or arylalkenylketone in which thearyl group is optionally substituted, or a heteroaryl ketone.
 11. Thecompound according to claim 1, wherein Y^(II) is a phenyl group at leastmono-substituted with —CHO, a ketone, an aldehyde, —CH═CH—CHO,—C(alkyl)=N—OH, —C(alkyl)=N—O(alkyl) and other keto derivatives,—CH═N—OH, —CH═NO(alkyl) and other aldehyde derivatives,—C(cycloalkyl)=NOH, —C(cycloalkyl)=N—O(alkyl).
 12. The compoundaccording to claim 1, wherein the compound is selected from the groupconsisting of: 3-Phenylpropyl 3-piperidinopropyl ether3-(4-Chlorophenyl)propyl 3-piperidinopropyl ether 3-Phenylpropyl3-(4-methylpiperidino)propyl ether 3-Phenylpropyl3-(3,5-cis-dimethylpiperidino)propyl ether 3-Phenylpropyl3-(3,5-trans-dimethylpiperidino)propyl ether 3-Phenylpropyl3-(3-methylpiperidino)propyl ether 3-Phenylpropyl 3-pyrrolidinopropylether 3-(4-Chlorophenyl)propyl 3-(4-methylpiperidino)propyl ether3-(4-Chlorophenyl) propyl 3-(3,5-cis-dimethyl piperidino)propyl ether3-(4-Chlorophenyl) propyl 3-(3,5-trans-dimethyl piperidino)propyl etherand pharmaceutically acceptable salts, hydrates, or hydrated salts, ofthese compounds or the polymorphic crystalline structures of thesecompounds or their optical isomers, racemates, diastereoisomers orenantiomers.
 13. The compound according to claim 1, wherein the compoundis 3-(4-chlorophenyl)propyl-3-piperidinopropylether, or itspharmaceutically acceptable salts, hydrates, or hydrated salts, or thepolymorphic crystalline structures of this compound or its opticalisomers, racemates, diastereoisomers or enantiomers.
 14. The compoundaccording to claim 13, in the form of a pharmaceutical salt chosen fromthe group consisting of hydrochloride, hydrobromide, hydrogen maleateand hydrogen oxalate.
 15. A pharmaceutical composition comprising acompound of formula (IIa) as defined in claim 1 with a pharmaceuticallyacceptable vehicle or excipient.
 16. The pharmaceutical compositionaccording to claim 15 comprising3-(4-chlorophenyl)propyl-3-piperidinopropylether or its pharmaceuticallyacceptable salts, hydrates, or hydrated salts, or the polymorphiccrystalline structures of this compound or its optical isomers,racemates, diastereoisomers or enantiomers with a pharmaceuticallyacceptable vehicle or excipient.
 17. A method for treating CNS diseasesor conditions comprising administering, in an amount effective toinhibit H3 receptor activity, a compound of formula (IIa) as defined inclaim 1 to a patient in the need thereof.
 18. The method according toclaim 17 using 3-(4-chlorphenyl)propyl-3-piperidinopropylether, or itspharmaceutically acceptable salts, hydrates, or hydrated salts, or thepolymorphic crystalline structures of this compound or its opticalisomers, racemates, diastereoisomers or enantiomers.
 19. The method oftreatment according to claim 17, wherein the CNS diseases or conditionsare selected from the group consisting of Alzheimer disease, attention,wakefulness and/or memorization disorders.
 20. The method according toclaim 17, wherein the CNS diseases or conditions are selected from thegroup consisting of cognitive deficits in psychiatric pathologies. 21.The method according to claim 19 for the treatment of disorders in agedpersons, depressive or asthenic states.
 22. The method according toclaim 17, for the treatment of obesity, vertigo and motion sickness. 23.A method for treating psychosomatic disorders, respiratory, allergicand/or inflammatory conditions, cardiac conditions, gastrointestinalconditions, conditions of the urogenital system, conditions of thecutaneous system comprising administering an effective amount of acompound of formula (IIa) as defined in claim 1 to a patient in the needthereof.
 24. The method according to claim 23 for treating sleepdisorders, stress, migraine, headache, pain, psychotropic disorders,asthma, bronchitis, rhinitis, tracheitis, gastric or duodenal ulcers,ulcerative colitis, Crohn's disease, irritable bowel syndrome, cystitis,metritis, urinary and faecal incontinence, urticaria, itching,arthritis, conjunctivitis, premenstrual syndrome, prostaticinflammations, genital disorders, rheumatic and ocular conditions,sialorrhea, convulsion, depression, disorders of thehypothalamohypophyseal secretion, the cerebral circulation and/or immunesystem.